IE62715B1 - Combination therapy for treatment of estrogen sensitive diseases - Google Patents

Combination therapy for treatment of estrogen sensitive diseases

Info

Publication number
IE62715B1
IE62715B1 IE84690A IE84690A IE62715B1 IE 62715 B1 IE62715 B1 IE 62715B1 IE 84690 A IE84690 A IE 84690A IE 84690 A IE84690 A IE 84690A IE 62715 B1 IE62715 B1 IE 62715B1
Authority
IE
Ireland
Prior art keywords
inhibitor
pharmaceutical composition
secretion
treatment
antiestrogen
Prior art date
Application number
IE84690A
Other versions
IE900846L (en
Inventor
Fernand Labrie
Original Assignee
Endorecherche Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Endorecherche Inc filed Critical Endorecherche Inc
Publication of IE900846L publication Critical patent/IE900846L/en
Publication of IE62715B1 publication Critical patent/IE62715B1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

A method of treatment of breast and endometrial cancer in susceptible warm-blooded animals may include inhibition of ovarian hormonal secretion by surgical (ovariectomy) or chemical (use of an LHRH agonist, e.g. [D-Trp6, des-Gly-NH210]LHRH ethylamide or antagonist) as part of a combination therapy comprising administering an antiestrogen together with at least one compound selected from the group consisting of an androgen, a progestin, at least one inhibitor of sex steroid formation, especially 17 beta -hydroxysteroid dehydrogenase and aromatase activity, at least one inhibitor of prolactin secretion, one inhibitor of growth hormone secretion and one inhibitor of ACTH secretion. Pharmaceutical compositions useful for such treatment and pharmaceutical kits containing such composition are disclosed.

Description

OF ESTROGEN SENSITIVE DISEASES This invention relates to kits for treatment of breast and endometrial cancer in susceptible warm-blooded animals including humans and in particular to kits comprising anti-estrogens in combination with other inhibitors of hormone production, inhibitors of hormone functions and/or in combination with other hormones.
Various investigators have been studying hormone-dependent breast and endometrial cancer. A known for®, of endocrine therapy in premenopausal women is castration most commonly preformed by surgery or irradiation, two procedures giving irreversible castration. Recently, a reversible form of castration has been achieved by utilizing Luteinizing Hormone Releasing Hormone agonists ("LHRH agonists") which, following inhibition of secretion of bioactive Luteinizing Hormone CSLH) by the pituitary gland, decrease serum estrogens to castrated levels (Nicholson et al., Brit. J. Cancer 39, 268-273, 1979).
Several studies show that treatment of premenopausal breast cancer patients with LHRH agonists induces responses comparable to those achieved with other forms of castration (Klijn et al., J.
Steroid Biochem. 20 1381, 1984; Nanni et al., Endocr. Rev. 7: 89-94; 1986). Beneficial effects of treatment with LHRH agonists have also been observed in post-menopausal women (Nicholson at al., J. Ster. Biochem. 23, 843-848, 1985).
A.V. Schally et al., Cancer Treatment Reports, 68 (No. 1) 281-289 (1984), summarize the results of animal and clinical studies on growth inhibition of hormone-dependent mammary and prostrate tumors by use of - 2 analogues of luteinizing hormone-releasing hormone, the so-called LHEH agonists and suggest that LHRH analogs and/or antagonists may have potential for treating breast cancer.
T. W. Redding and A.V. Schally, Proc. Natl Acad. Sci. USA, SG, 14551462 (1983) disclose reduction of estrogen-dependent lasemary tumors In rats and mice by use of an LHRH agonist (D-Trp®J LHRH or of two specific antagonists.
In U.S. Fat. No. 4,071.622,, it is disclosed that use of certain LHSH agonists causes regression of DMBA-induced mansaaxy carcinoma in rats.
U. S. Pat. No. 4,775,660 relates to the treatment of female breast cancer by use of a combination therapy comprising administering an antiandrogen, and an antiestrogen to a female after the hormone output of her ovaries has been blocked by chemical or surgical means.
U.S. Pat. No. 4,775,661 relates to the treatment of female breast cancer by use of a therapy comprising administering to a female after the hormone output of her ovaries has been blocked by chemical or surgical means an antiandrogen and optionally an inhibitor of sex steroid biosynthesis .
U.S. Pat. No. 4,760,053 describes a treatment of selected sex steroid dependent cancers which combines an LKRH agonist and/or an antiandrogen and/or an antiestrogen and/or at least one inhibitor of sex steroid biosynthesis.
In U.S. Pat. No. 4,472,382, it is disclosed that prostatic adenocarcinoma, benign prostatic hypertrophy and hormone-dependent mammary tumors may be treated with various LH-RH agonists and that prostate adenocarcinoma and benign hypertrophy may be treated by use of various LHRH agonists and an antiandrogen. However, there is no suggestion or disclosure of the present invention.
Some clinical improvement in premenopausal women with breast cancer by use of the two LHRH agonists, Buserelin and Leuprolide, is also reported by H.A. Harvey et al. LH-RH analogs in the treatment of human breast cancer , LHRH and its Analogs — A new Class of contraceptive and therapeutic Agents (B.H. Vickery and J.J. Nestor, Jr., and E.S.E. Hafez, eds) Lancaster, MTP Press, (1984), and by J.G.M. Klijn et al. Treatment with luteinizing hormone-releasing hormone analogue (Buserelin) in premenopausal patients with metastatic breast cancer, Lancet 1, 12131216 (1982).
Androgen receptors have been demonstrated in human breast cancer samples (Engelsroan et al., Brit. J. Cancer 30. 177,1975; Lippsan et al., Cancer 38, 868-074, 1976; Maass et al., J. Steroid Biochem. 6, 743-749, 1975) and in human breast cancer cell lines including MCE-7 cells (Lippman et al. , Cancer Res. 36» 4610-4618» 1976). Recent reports have indicated that androgen receptors may add to the selective power of estrogen receptors (ER) or even supplant ER towards predicting response to endocrine therapy (Bryan et al., Cancer 54,., 2436-2440, 1984; Teulings et al. , Cancer Res. 40: 2557-2561, 1980).
The first androgen successfully used in the treatment of advanced breast cancer is testosterone propionate (Nathanson, Rec. Brogr. Kota. Res, 1, 261-291, 1947). Many studies subsequently confirmed the beneficial effect of androgens on breast cancer (Adair, Surg. Gynecol. Obstet. 84, 719-722,' 1947; Alan and Herman, Ann. Surg. 123, 1023-1035» 1946; Adair et al., JAMA 140, 1193-2000» 1949). These initial results stimulated cooperative studies on the effect of testosterone propionate and DES which were both found to be effective in producing objective remissions.
(Subcommittee on Steroids and Cancer of the Committee on Research ot the Council on Pharmacy and Chemistry of the Am. Med. Association followed by the Cooperative Breast Cancer Group under the Cancer Chemotherapy National Service Center of the NCI who found that testosterone propionate improved remission rate and duration, quality of life and survival (Cooperative Breast Cancer Group, JAMA 188, 1069-1072, 1964).
A response rate of 48% (13 of 27 patients) was observed in postmenopausal women who received the long-acting androgen methono lone enanthate (Kennedy et al., Cancer 21, 197-201, 1967). Th® median duration of survival was four times longer in th© responders as compared to the non-resΊθ ponder group (27 versus 7.5 months). A large number of studies have demonstrated that androgens induce remission in 20 to 40% of women with metastatic breast cancer (Kennedy, Hormone Therapy in Cancer. Geriatrics 25, 106-112, 1970; Goldenberg et al., JAMA 223, 1257-1268, 1973).
The combination Fluoxymesterone and Tamoxifen has been shown to be ζ superior to Tamoxifen alone. In fact, complete responses (CR) were seen only in the combination arm while 32% showed partial response (PR) in th® combination arm versus only 15% in the monotherapy arm. In addition, there were only 25% non-responders in the combination therapy arm versus 50% in the patients who received TAM alone (Tonney et al., Ann. Int. Med. 98, 139-144, 1983). Moreover, the median time from onset of therapy to treatment failure was longer with Fluoxymesterone + Tamoxifen (180 days) compared to the Tamoxifen arm alone (64 days). There was a tendency for improved survival in the combination therapy arm (380· versus 330 days).
The independent beneficial effect of an antiestrogen combined with an androgen is suggested by the report that patients who did not respond to Tamoxifen could respond to Fluoxymesterone and vice versa. Moreover, patients treated with Tamoxifen and crossing over to Fluoxymesterone survived longer than the reverse regimen (Torraey et al., Ann. Int. Hed. 98, 139-144, 1983). Recent in vitro studies compose the relative antiproliferative activities of an antiestrogen and an androgen on the growth cf the estrogen-sensitive human mammary carcinoma cell line ZR.-75-1 (Poulin ec al. '’Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-I human breast cancer cell line» Breast Cancer Res. Treatra. 12, 213-225, 1989a).
A response rate of 39% with an average duration of 11 months has recently been observed in a group of 33 postmenopausal women who previously failed or did not respond to Tamoxifen. (Hanni et al.» Cancer 48: 2507-2509, 1981) upon treatment with f luoxymesterone (Halostatin) (10 mge b.i.d.). Of these women, 17 had also undergone hypophysectomy. There was no difference in the response rate to Fluoxyrcesterone in patients who had previously responded to Tamoxifen and in those who had failed. Of the 17 patients who had failed to both Tamoxifen and hypophysectomy, 7 responded to Fluoxymesterone for an average duration of 10 months. Among these, two had not responded to either Tamoxifen and hypophysectomy.
Also, combination of Tamioxifen with Sandostatin, an inhibitor of growth hormone secretion, induced a growth inhibitory effect in MCF-7 and TU70 cells (Resnicoff et al. Endocinology Abstract N° 930, Proceedings of AACR, Vol 29, March 1988). - 5a Since testosterone propionate had beneficial effects in both preand postmenopausal women (Adair et al. „ J. Am. Med. Ass. 15: 1193-1200; 1949)s if indicates that in addition to inhibiting gonadotropin secretion, the androgen exerts a direct inhibitory affect on cancer growth.
As mentioned above, Poulin et al. (Breast Cancer Res. Treats. 12, 213-225, 1989a) have found that the growth of ZR-75-1 human breast carcinoma cells is inhibited by androgens, the inhibitory effect of androgens being additive to that of an antiestrogen. The inhibitory effect of androgens on the growth of human breast carcinoma cells ZR-75-1 has also been observed in vivo in nude mice.
Many clinical trials have shown the benefits of medroxyprogesterone acetate (MPA) in breast cancer therapy (Cavalli et al. , J. Clin. Oncol. 2, 414, 1984; Van Veelen ef al., Cancer 58, 713, 1986; Johnson et al., Brit. J. Cancer 50, 363, 1984; Rabustelli della Cuna, G. Comprehensive guide co the therapeutic use of medroxyprogesterone acetate in oncology, Farmitalia Carlo Erba, S.P.A., 1987).
Poulin et al. 13Androgen and glucocorticoid receptor-mediated inhibition of ceil proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells" , Breast Cancer Res. Treatm., 1989b,» in press) have recently found that the inhibitory effect of medroxyprogesterone acetate (MPA) on the growth, of the human ZR-75-1 breast cancer cells is mainly due to the androgenic properties of the compound. The androgenic properties of MPA have been clearly demonstrated in other systems (Labrie, C. et al.. J. Steroid Biochem. 28: 379-384, 1987; Luthy et al., J. Steroid Biochem. 31: 845-852, 1988; Plante st al., J'. Steroid Biochem., 31, 61-64,, 1988). Other synthetic progestins have also been shown to possess, in addition to their progesterone-like activity, various degrees of androgenic activity (Labrie et al., Eertil. Steril. 31, 29-34, 1979; Poyet and Labrie, The Prostate 9, 237-246, 1986; Labrie, C. et al., J. Steroid Biochem. 28: 379-384, 1987; Luthy ef al., J. Steroid Biochem. 31: 845-852, 1988; Plante et al., J. Steroid Biochem. 31, 61-54, 1988).
Poulin et al. Inhibition of estrogen-dependent cell proliferation by the synthetic progestin R5020 and antagonism of progestin action by insulin in ZR-75-1 human breast cancer cells, Breast Cancer Res. Treatm., 1989c, in press),, have observed that 17 ,21-di:sefhyl-19nor4,9-oregnadiene-3,20-dione (’’R502Q, promegestone) and progesterone itself can inhibit the growth of the human breast cancer cell line ZR-75-1 by an action mediated by the progesterone receptor. R5020 has been found to inhibit the growth of normal human breast cancer cells in culture in the presence as well as in the absence of Es (Compel at al., J. Clin. Endocrinol. Metab. 63, 1174-1180, 1986).
H. Houridsen et al.. Cancer Treats. Rev. 5, 131-141, (1978) dis close that Tamoxifen, an antiestrogen, is effective in remission of advanced breast cancer in about 30% of the women -patients treated.
J.G.M. Klijn et al., (J. Steroid Bioehem.„ 20 (No. 6B) , 1381 (1984), disclosed the combined use of tha antiestrogen,, Tamoxifen, and the LHRE agonist, Buserelin, for treatment of breast cancer is known but objective remission of such cancers remains low <35X3..
Various steroids have been described as irreversible aromatase inhibitors, including 4-hydroxy-4-androstene~3,17-dione (Brodie et al., Steroids 38: 693-702, 1981; Covey and Hood, Cancer Res. 42; Suppl. 3327s-3333s, 1982), androsta-4,6-triene-3,17-dione (Covey and Hood, Endocrinology 108, 1597-1599, 1981), MDL 18962 (Johnston et al., Endocrinology 115, 776-785, 1984). SH 489 (Henderson et al., J. Steroid Bioehem. 24, 303-306, 1986) and 6-methylenandrosta-l ,4-diene-3,17-dione (FCS 24304) (Giudici et al., J. Steroid Bioehem. 30: 391-394, 1988).
Huggins and Bergenstal (Cancer Res. 12, 134-141, 1952) have observed that adrenalectomy could induce remission in breast cancer patients who had failed after castration. Treatment of advanced breast cancer with aminoglutethimide after therapy with the antiestrogen Tamoxifen is disclosed by A.V. Buzdar et al. Cancer 50, 1708-1712 (1982).
High doses of ketoconatole can inhibit 17a-hydroxylase and C17-20lyase (Santen et al., J. Clin. Endocrinol. Metab. 57, 732-736, 1983) while 16-methylene estrone can inhibit the 17β-Η50 step (Thomas et al., !· J. Biol. Chem. 258, 11500-11503, 1983).
Trilostane and epostane have been described as inhibitors of 3βhydroxy-steroid dehydrogenase activity (Erashaw et al., Clin. Endocrinol. 21» 13-21, 1984; Robinson et-al.» J. Steroid Biochem. 21, 501-605,, 1984; Lambert et al., Ann. Clin. Biochem. 23 , 225-229, 1986; Potts et al., Steroids 32, 257-267, 1978) and have been successfully used for the treatment of breast cancer in combination with corticosteroids (Beardwell et al.» Cancer Chemother. Pharmacol. 10: 158-160, 1983; Williams et al., Cancer Treat. Rep. 71, 1197-1201, 1987). 4-MA, (17p-N,N-diethylcarbamoyl-4-methyl-4-a2a-5a-androstan-3-one) has been found to inhibit Sp-hydroasysteroid dehydrogenase activity in granulosa cells (Chan ec al., Biochem. Biophys. Res. Common. 144» 166171» 1987). Epostane has been shown to inhibit. 3β-hydroxysteroid dehydrogenase activity in pregnant goats (Taylor, J. Endocrinol. 113, 489-493» 1987).
A synthetic androgen, methyltrienolone has been reported to inhibit the growth of endometrial carcinoma cells in culture (Centola. Cancer Res. 45: 6264-6267» 1985). Medroxyprogesterone acetate is successfully used for the treatment of endometrial cancer (Ayoub et al., Gynecol. Oncol. 31(2): 327-337» 1988).
Prolactin and growth hormone have been shown to stimulate colony formation of the NMu rat maisaary tumor cultured in vitro in the soft agar clonogenic assay (Manni and Wright» J. Natl Cancer Inst. 74» 941-944. 1985).
Prolactin is known to play a role in stimulating carcinoma in exper25 imental animals, especially mammary carcinoma induced in the rat by diraethylbenz(a) anthracene (DMBA) (Welch et al.» Cancer Res. 30» 1024-1029 1970). A study of 30 women suffering from breast cancer showed I / ΊΟ that 10 became pain-free upon treatment with, L-Dopa, an inhibitor of prolactin secretion (Minton, Cancer 33, 358-363, 1974). In these 10 women, there were objective and subjective signs of tumor control.
A problem with prior art treatments is a lack of effective simultaneous control of both beneficial and detrimental hormones.
Moreover, effective control of detrimental hormones (i.e. those hormones which may stimulate tumor growth) often requires closing down a plurality of pathways. Prior art treatments have tended to foreclose only particular synthetic pathways, leaving other pathways available for formation of the undesired hormone. Other treatments have attempted to block, the activity of detrimental hormones such as estrogens. However, because such blocking is difficult to completely achieve, the formation of the estrogens, together with incomplete blocking, enable some estrogens to bind and undersirably activate receptors. This necessarily diminishes the effectiveness of treatment.
It is an object of the present invention to provide a therapeutic combination, e.g. a kit, for treatment of breast cancer and endometrial cancer wherein the treatment selectively inhibits the formation and/or action of hormones which would otherwise contribute to tumor growth, while maintaining those which do not increase growth and are otherwise beneficial to general health.
It is another object of the invention to provide a therapeutic combination, e.g. a kit, for treatment having increased effectiveness in slowing or reversing tumor growth.
\ It is another object of the invention to provide therapeutic combination, e. g. a kit, for treatment of breast or endometrial cancer having significantly reduced frequency of unwanted side effects.
According to th® present invention there is provided a kit for treatment of breast or endometrial cancer, said kit including a pharmaceutical composition comprising axx anti estrogen and at least on© pharmaceutical composition selected from the group consisting of a pharmaceutical composition comprising an inhibitor of sex steroid formation chosen from the group consisting of an inhibitor of aromotase, an inhibitor of 3β - hydroxysteroid ns4-isomerase and an inhibitor of 17β - estradiol dehydrogenase, a pharmaceutical composition comprising an inhibitor of ACTH secretion and a pharmaceutical composition comprising an inhibitor of growth hormone secretion.
There is also provided a kit for treatment of breast or endometrial cancer, said kit including a pharmaceutical composition comprising an inhibitor of ovarian hormonal secretions, a pharmaceutical composition comprising an antiestrogen, and at least one pharmaceutical composition comprising a compound selected from the group consisting of a pharmaceutical composition comprising an inhibitor of sex steroid formation chosen from the group consisting of an inhibitor of aromotase, an inhibitor of 3β 11 hydroxysteroid δ5-δ*-isomerase and an inhibitor of 170 - estradiol dehydrogenase, an androgenic compound, an inhibitor of growth hormone secretion and an inhibitor of AGTH secretion.
In a further aspect of the present invention there is provided a pharmaceutical composition for treatment of breast or endometrial cancer comprising a therapeutically. affective amount of ..an. .anti estrogen and of at least one pharmaceutical compound selected from the group consisting of an inhibitor of aromatase, an inhibitor of 3β - hydroxysteroid δs-δ4-isomerase and an inhibitor of 17β estradiol dehydrogenase.
The present invention further provides a pharmaceutical composition for treatment of breast or endometrial cancer including a pharmaceutical composition comprising an inhibitor of ovarian hormonal secretions, an antiestrogen, and at least one compound selected from the group consisting of an inhibitor of aromatase, an inhibitor of 3β - hydroxysteroid δ ’-Δ -isomerase and an inhibitor of 17β estradiol dehydrogenase and, an androgenic compound.
The invention also provides corresponding uses of an antiestrogen in the manufacture of pharmaceutical compositions as defined in claims 10 to 17.
Figure 1 is a schematic representation of the sites of action of drugs active in the treatment of breast cancer. The following abbreviations are used: ER: estrogen receptor; ASLz androgen receptor; PR: progesterone receptor; GR; glucocorticoid receptor; DE2AS: dehydroepiandrosterone sulfate; DKEA: dehydroepiandrosterone; AK-diol androst-5-ene3β,17β-άΐο1; d^-dione, androstenedione; E,: estrone; E,: lip-estradiol; T: testosterone; DHT: dihydrotestosterone; E,S: E.-sulfate; Et-S: E, sulfate; (1) LHKK-A: luteinizing hormone-releasing hormone agonist or antagonist; (2) ANTl-E: antiestrogen; (3) AND: androgen; (4) PROG; progestin; (5) 17β-Η50: inhibitor of 17β-estradiol steroid dehydrogenase or 17p~hydroxysteroid dehydrogenase; (6) AROs inhibitor of aromatase activity; (7) 3β~Η5Ώ: inhibitor of 3β-hydroxysteroid, dsA% isomerase; (8) INH: inhibitor of adrenal steroidogenesis; (9) PRE: inhibitor of prolactin secretion; (10) GH: inhibitor of growth’hormone secretion; (113 AGTH: inhibitor of AGTH secretion.
Referring to Figure I, the "+"s and "-"s next to each indicated receptor designate whether activation of that receptor aids or hinders tumor growth. As may be seen from Figure 1, activation of the estrogen receptor will stimulate tumor growth, and is therefore to be prevented. However, it is important to continue to activate the androgen receptor, whose activation may inhibit tumor growth. Likewise, it is desirable to continue to activate the progesterone and glucocorticoid receptors.
One method of inhibiting activation of the estrogen receptor is treatment with an effective antiestrogen compound having an affinity for the receptor site such that it binds the receptor site and blocks estrogen from binding and activating the site. It is important to select antiestrogens which tend to be pure antagonists, and which have no agonistic activity. Otherwise, the antiestrogen which blocks the receptor site from estrogen, may itself activate the site. Preferred antiestrogens are discussed in detail below. Because it is extremely difficult to block all receptor sites, it is desirable to simultaneously decrease the concentration of estrogen available fo activate estrogen receptors. Hence, it is desirable to inhibit production of estrogen by the, ovaries. This nay be accomplished in a variety of ways including surgical removal of the ovaries, irradiation of the ovaries, or by chemical means. Chemical means include but are not limited to the use of agonists or antagonists of luteinizing hormone releasing hormone. These compounds act on the pituitary in a manner effective to stop its production of bioactive luteinizing hormone, a hormone necessary fo cause the ovaries to produce and secrete estrogen and/or other hormones which may be converted to estrogen.
As may ba seen from the scheme of Figure 1, a number of hormones released by the adrenals may be converted by a variety of biological pathways into estrogen. Among the estrogens thus produced are Upestradiol and androst-5-ene-3β,17β-άίο1. It is therefore highly desirable to include an inhibitor of l/p-estradiol dehydrogenase or 17βhydroxy steroid dehydrogenase. Such inhibitors close down the synthetic pathways crossed by vertical line 5 denoted 17p-HSD" on Figure 1. Hence synthesis of both major forms of estrogen shown on Figure 1 is substantially prevented. Other sex steroid formation inhibitors such as inhibitors of 3p-hydroxy steroid or of aromatase activity are also preferably included in treatment in order to close down the synthetic pathways crossed hy the two horizontal lines 6 and 7 denoted ARO and 3B-HSD, respectively.
Xt will be noted that the foregoing methods of inhibiting estrogen synthesis also have the undesirable effect of inhibiting androgen synthesis. Because androgens are beneficial to retarding tuaor growth, it is desirable to administer (add block) androgens in connection with any of the foregoing treatments which inhibit sex steroid synthesis. Other preferred additions co treatment include W progestins, inhibitors of growth hormone secretion, inhibitors of prolactin secretion and inhibitors of adrenal corticotrophin hormone secretion. The latter has the effect of preventing ACTH from reaching the adrenals and thus of preventing the adrenals fro® synthesizing and secreting compounds such as dehydroepiandrosterone sulfate, a precursor of the synthesis of estrogen. Alternatively, inhibitors which close down synthetic pathways in the adrenals will achieve the same result. When adrenal secretions are inhibited or stopped, essential glucocorticoids should be added back as part of the therapy.
In one embodiment, the invention provides a kit for treatment of breast and endometrial cancer in a warm-blooded animal in need of such treatment, said treatment comprising inhibiting the ovarian hormonal secretions of said animal by surgical, radiotherapeutical or chemical means and administering to said animal said kit comprising therapeutically effective amounts of an antiestrogen and at least one compound selected from the group consisting of an androgen, a progestin, at least one inhibitor of sex steroid formation, one inhibitor of prolactin secretion, one inhibitor of growth hormone and one inhibitor of ACTH secretion or mixtures - 15 thereof.
Xn. certain, embodiments, the invention provides a kit for treatment of breast cancer, comprising a therapeutically effective amount (1) of an antiestrogen and a progestin, (2) of an antiestrogen and at least one inhibitor of sex steroid biosynthesis, (3) of an antiestrogen, an androgen and a progestin, (4) of an antiestrogen, an androgen and at least one inhibitor of sex steroid biosynthesis, (5) of an antiestrogen, a progestin and at least one inhibitor of sex steroid biosynthesis, (6) of an antiestrogen, an androgen, a progestin and at least one inhibitor of sex steroid biosynthesis, (7) of an antiestrogen, an androgen, and at least one inhibitor of prolactin secretion and/or growth hormone secretion and/or ACTH secretion, (8) an antiestrogen, a progestin and at least one inhibitor of prolactin secretion and/or growth hormone secretion and/or ACTH secretion, (9) an antiestrogen, at least one inhibitor of sex steroid formation and at least one inhibitor of prolactin secretion and/or growth hormone secretion and/or ACTH secretion, (10) an antiestrogen, an androgen, a progestin and at least one inhibitor of prolactin secretion and/or growth hormone secretion and/or ACTH secretion, (11) an antiestrogen, an androgen, at least one inhibitor of sex steroid formation and at least one inhibitor of prolactin secretion and/or growth hormone and/or ACTH secretion, (12, an antiestrogen, a progestin, at least one inhibitor of sex steroid formation and at least one inhibitor of prolactin secretion and/or growth hormone secretion and/or ACTH secretion, (13) an antiestrogen, an androgen, a progestin, at least one inhibitor of sex steroid formation and at least one inhibitor of prolactin secretion and/or growth hormone secretion and/or ACTH secretion. ί In one aspect, the invention provides a kit for treatment of - 16 breast or endometrial cancer in a warm-blooded female animal in need of such treatment comprising therapeutically effective amount of an antiestrogen, an androgen and a blocker of steroid biosynthesis or a pharmaceutical composition thereof. The ovarian hormonal secretions of said animal can be blocked by surgical or chemical means. In on® aspect, the invention provides a kit for treatment of cancer in a castrated warm-blooded female animal (i.e. one whose ovaries are blocked by surgical or chemical means from secreting estrogen) which comprises an antiestrogen and an androgen or pharmaceutical compositions thereof, which is administered in amounts sufficient to treat such cancers.
In certain embodiments, the ovaries may be surgically removed (oophorectomy) but preferably the secretion of hormones from the ovaries is blocked chemically by administering an effective amount of an LHRH agonist or antagonist. In one preferred aspect, the present invention provides a kit for treatment of breast and endometrial cancer in a warm-blooded animal, comprising an LHRH agonist or antagonist, an antiestrogen, an androgen, and at least one inhibitor of sex steroid formation, or pharmaceutical compositions thereof, in amounts sufficient to treat breast and endometrial cancer.
Xn its preferred aspect, the LHRH agonist is administered parenterally (subcutaneously or intramuscularly) and the androgen, antiestrogen, and at least one inhibitor of sex steroid formation and each administered orally. The invention also provided kits or single packages combining the preferred pharmaceutical compositions of the invention. For example, a three-component kit provides an LHRH agonist parenteral pharmaceutical composition, an androgen oral pharmaceutical composition and an antiestrogen oral composition. A - 17 four-component kit may provide, for example, an LHRH agonist parenteral pharmaceutical composition, an antiestrogen oral pharmaceutical composition, an androgen oral composition and a steroid biosynthesis inhibitor oral composition. In certain preferred embodiments, the antiestrogen itself also acts ss a sex steroid inhibitor, and the kit need only contain one pharmaceutical composition for achieving both functions.
Thus, this invention leads to a novel method for effective treatment of breast and endometrial cancer. In addition, the amounts of anfciestrogen administered in this combined therapy are lower than normally used in the prior art, s.g. J.G.M. Klijn et al., J. Steroid Biochem. 20 (no. 6B) 1381 (1984), to treat breast cancer, and thus, the harmful effects of relatively large doses of antiestrogen are minimised.
Sy combining an optimal blockade of estrogen formation and/or action and the inhibitory effect of androgens on breast and endometrial cancer cell growth, a method of maximally inhibiting the growth of breast and endometrial cancer may be obtained.
In female mammals, it is preferred that an inhibitor of ovarian hormonal secretions is used, e.g. an effective amount of an LHRH agonist or antagonist.
In its preferred aspect, the LHRH agonist is administered parenterally (subcutaneously or intramuscularly or intranasally) and, in association therewith, the antiestrogen, the androgen and the inhibitor of sex steroid biosynthesis are each administered orally.
In another preferred aspect, the antiestrogen, androgen and/or inhibitor of sex steroid biosynthesis are administered in a controlled release formulation. - 18 In one preferred aspect, the present invention provides a kit for treatment of breast and endometrial cancer in warm-blooded female animals in need of such treatment comprising an LHRH agonist or antagonist, in association with an antiestrogen, a progestin, an androgen and an inhibitor of sex steroid biosynthesis or pharmaceutical compositions thereof in amounts sufficient to inhibit tumor growth. These active compounds can. be administered together or in any order as discussed hereinafter.
To assist in determining the effect of the treatment, blood plasma concentrations of the sex steroids of adrenal and ovarian origin, i.e., precursor steroids, androgens and estrogens, and tumor size are measured. Lowered concentrations of sex steroids and reduction in tumor size are indicative of successful treatment, e.g. inhibition of tumor growth using active compounds described herein in accordance with the present invention. The concentrations of adrenal androgens and estrogens such as dehydroepiandrosterone (DHEA), DHEA-S sulfate (DHEAS), androst-5-ene-3ft,1"β-diol (A5-diol) and, the ovarian estrogen, 17β-estradiol Cty sre measured by standard methods well known to those skilled in the art, see for example, E. Labrie et al., The Prostate 4, 579-584, 1983: Luthy et al., J. Gynecol. Endocrinol., 1, 151-158, 1987).
The change in tumor size is measured by standard physical methods well known to those skilled in the art, e.g., bone scan, chest X-ray, skeletal survey, ultrasonography of the liver and liver scan (if needed), CAT-scan and physical examination.
While a LHRH agonist or a LHRH antagonist may be used in cne preferred aspect of the present invention, the use of a LHRH agonist is more preferred.
By the term LHRH agonist is meant synthetic analogues of the natural luteinizing hormone-releasing hormone (LHRH)» for example, a decapeptide of the structure: L-pyroglutamyl-L-histidyl-L-tryptophyl-Lseryl-L-tyrosyl-glycyl-L-leucyl- L-arginyl-L-propylglycyl-NK3. Suitable LHRH agonists include nonapeptides and decapeptides represented by the formula: L-pyroglutanryl-L-histxdyl-L-ttTptophyl-L-seryl-L-tyrosyl-X-yarginyl-L-prolyl-Z wherein X is D-tryptop’nyl, D-leucyl, D-alanyl» iminobenzyl-D-histidyl „ 3~(2-naphthyl)-D-alanyl, O-tert-butyl-D-seryl, D-tyrosyl, Π-lysyl» D-phenylalanyl or N-methyl-D-alanyl and Y is L-leucyl, D-leucyl, Ns-methyl D-leucyl, N~-methyI~L~leucyl or D-alanyl and wherein Z is glycyl-NHR, or NHRX wherein Rx is H, lower alkyl or lower haloalkyl. Lower alkyl includes straight- or branched-chain alkyls having 1 to 6 carbon atoms, e.g., methyl ,· ethyl» propyl, pentyl or hexyl» isobutyl, neopentyl and the like. Lower haloalkyl includes straight- and branched-chain alkyls of 1 to 6 carbon atoms having a halogen substituent, e.g., -Cs3„ -CH.CFj, -CFjCHj. Halogen means F, Cl, Br, I with Cl being preferred.
In preferred nonapeptides» Y is L-leucyl, X is an optically active D-form of tryptophan, serine (t-BuO), leucine, histidine (iminobenayl)» and alanine.
Preferred decapeptides include (D-Trp*]-LHKH wherein X^D-Trp,' Y»Lleucyl, Z=glycyl-HH.„ [D-Phe*]LHRH wherein X-D-phenylalanyl„ Y-L-leucyl and 2=glycyl-HN,) or [D-Nal(2)6]LHRH which is [(3-(2-naphthyl)~D-Ala*]LHRH wherein X=3-(2-naphthyl)-D-alanyl, Y=L-leucyl and 2=glycyl-NH,).
Other LHRH agonists useful within the scope of this invention are the C-3.ZS. analogues of the natural LH-RH, especially, [D-?he6, Atgly’8)LHRH, [D"Tyr(Me)s, Azgly10]-LHRH„ and (D-Ser-(t-BuO)6„ Azgly3»] -LHRH disclosed by A.S. Dutta et al. in j. Med. Chem., 21, 1018 (1978) and U.S. Pat. ' No. 4, 100,274 as well as those disclosed in U.S. Pat. Kos. 4,024,248 and 4,118,483.
Typical suitable LHRH antagonists include [N-Ae-D-p-Cl-Phe1-,3, D-?he3, D"Arg®3 D-Alal0]LHHH disclosed by J. Ercheggi et al., Bioehem. Biophys. Res. Commun. 1GQ. 915-920, (1981); [N-Ac-D-p-Cl-Phe3D-Trp3 , D-Args, D-Ala♦0]LHRH disclosed by D.H. Coy et al.. Endocrinology, 110: 1445-1447, (1982); [N-Ac-D-(3-( 2-naphthyl)-AlaP, D-p-Cl-Phe3, D-Trp3, D-hArg(Etj)4, D-Ala10]-LHRH and [H-Ac-Pro1, D-p-F-Phe3, (D-(3~(2~naphthyl) Ala3,sJ-LHRH disclosed by J.J. Nestor et al. J. Steroid Bioehem., 20 (No. 63) , 1366 (1984) ; the nona- and decapepcides analogs of LHRH useful *5 as LHRH antagonists disclosed in U.S. Pat. Ko. 4,481,190 (J.J.. Nestor et al.); analogs of the highly constrained cyclic antagonist, cycle [A’Pro1, D-p-Cl-Phe3, D-Trp3,®,, N-Me-Leu7, $-Alaie]LHRH disclosed by J. Rivier, J. Steroid Bioehem. , 20, (Ko. 63), 1365 (1984), and [N-Ac-D~(3-(2-naphthyl )Ala1, D-p-F-Phe3, D-Trp3, D-Arg*]-LHRK disclosed by A. Corbin et al., J.
Steroid Bioehem. 20 (No. 63) 1369 (1984).
Other LHRH agonist and antagonist analogs are disclosed in LHRH and its Analogues (B.H. Vickery et al. editors at page 3-10 (J.J. Nestor), 11-22 (J. Rivier et al.) and 23-33 (J.J. Nestor et al.).
The LHRH agonists and antagonists useful in this invention may conveniently be prepared by the method described by Stewart et al. in Solid Phase Peptide Synthesis (published in 1969 by Freeman & Co., San Francisco, page 1) but solution synthesis may also be used. ine nona- ana decapeptides used in this invention are conveniently X* assembled on a solid resin support, such as IX cross-linked Pro-Merrifield resin by use of an automatic peptide synthesizer. Typically, sidechain protecting groups, well known to those in the peptide arts, are used during the dicyclohexylcarbodiimide-catalyzed coupling of a tertbutyoxycarbonylamino acid to tha growing peptide attached to a benshydrylamine resin. The tert-butyloxycarbonyl protecting groups are removed at each stage with trifluoroacetic acid. The nona- or decapeptide is cleaved from tha resin and deprotected by use of KT. The crude peptide is purified by the usual techniques, e.g., gel filtration, HPLC and partition chromatography and optionally lyophilization. See also D.H. Cay st al., J. Med. Chem. 19, pages 423-452, (1976).
Typically suitable androgens include 6-alpha-sethyl,17-alpha-acstaxy progesterone or medroxyprogesterone acetate available, among others, from Upjohn and Farmitalia Carlo Erba, S.d.A- under the trade names, among others, of Provera and Farlutal, and the acronym MPA.
Other suitable androgens include other synthetic progestins as described in Labrie et al. (Fertil. Steril. 31: 29-34, 1979) as well as anabolic steroids or progestins (Raynaud and Ojasoo, in: Innovative Approaches in Drug Research. Elsevier Sc. Publishers, Amsterdam, pp. 47-72, 1986; Sandberg and Kirdoni, Pharmac. Ther. 36: 263-307, 1988; and Vincens, Siraard and De Lignieres, Las Androgenes. In: Pharmacologie Clinique, Base de Therapeutique, 2ieme edition, Expansion Scientifiaue (Paris), pp. 2139-2158, 1988), as well as Calusterone (7β,17c-dimethyltestosterone) , anabolic steroids (Lamb, Am. J. Sports Medicine 12, 31-38, 1984; Kilf, R. Anabolic-androgenic steroids and experimental tumors. In: (Kochacnian. C.D., ed.), Handbook of Experimental Pharmacology, vol. 43, Anabolic-Androgenic Steroids, Springer-Verlag, Berlin, 725 pp., 1975), fluoxymesterone (9a-fluoro-113~hydroxy-17a-raethyl testosterone), testosterone 173-cypionate, L7a-methyltestosterone , Pantestone (testosterone undecanoate) , Ax~testololactone and Andractim.
Typically suitable progestins include 17 .21-dimethyl-19- nor-4,9pregnadiene-3»2Q-dione (R5020, promegestone") available from RousselUCLAE as well as cyproterane acetate (Androcur) available from Schering AG, 6-aipha-methyl, 17-alpha-acetoxy progesterone or medroxyprogesterone acetate (M?A) available from, among others, Upjohn and Farmitalia, Calbo Erba, Gestoden available frcm Sharing, megestrol aceta te (17c-acetoxy~6methyl-pregna-4,6-diene-3,20-dione) available from Mead Johnson & Co.» Evansville, Ind. „ under the trade name of Megace. Other progestins include Levonorgestrel, Gestodene, desogestrel, 3-k.eto- desogestrel, norethindrone, norethisterone, 13c-ethyl-17-hydroxy"18,19- dinor-17ppregna-4,9,ll-triene-20-yn-3-one (R2323)» demegestone, norgestrienone. gastrinone, progesterone itself and others described in Raynaud and Ojasoo, J. Steroid Biochem. 25: 811-833. 1986; Raynaud et al., J. Steroid Biochem. 12: 143-157, 1980; Raynaud, Ojasoo and Labrie, Steroid Hormones, Agonists and Antagonists, In: Mechanisms of Steroid Action (G.P. Lewis and M. Ginsburg, eds), McMillan Press, London, pp. 145-158 (1981).
Typical suitable antiestrogens include those steroidal and non-steroidal antiestrogens such as (LRS,2RS)-4,4,-diacetoxy-5,5,-difluoro-(lethyl-Z-methyleneMi-ffl-phenylenediacetate, which is available from Biorex under the trade name of Acefluranol, Se.-chlQrQ-16ct-methyl-Qregn"4-’sne3,20-dione which is available from Eli Lilly &. Co.» Indianapolis, Ind. under the trade name of Cloraetherone, 5-chloro-17-hydraxypregna-l ,4,6triene-3,20-dione which is available as the acetate salt frcm Syntex Labs, Palo Alto, Cal. as Delmadione Acetate, 17-hydroxy-6-raethyl-19norpregna-4,6- diene-3,20-dione which is available from Tharamex under the name of Lutenyl, 1-[2-(4-[1-(4-methoxyphenyl)-2~nitro-2~phenylethenyl]phenoxy]ethyl]-pyrrolidine which is available as the citrate salt from Parke-Davis Qiv. of Warner-Lambert Co., Morris Plains, N.J. under the name of Nitroraifane Citrate, substituted arainoalkoxyphenylalkenes such as (Z) -2- (4-(1,2-diphenyl-1-butenyl) -phenoxy] -N ,Ν-dimethylethanamine which is available as the citrate salt from Stuart Pharmaceuticals, Wilmington. Del. as Tamoxifen Citrate (see also Belgian patent No. 637,389, Mar. 1964), 3,4-dihydro~2-(p-raethoxyphenyl)~l~naphthyl p—(2-(1pyrrolidinyl)ethoxy]phenyl ketone which is available as the methane sulfonate salt from Eli Lilly & Co. under the tradename of Trioxifene Mesylate, l-(4'-(2-phanyl)-bl-(31-hydroxyphenyl)-2-phenyl-but-l-sne which is available from Klinge Pharma, (6-hydroxy-2~(p-hydroxyphenyl)benzo(b)thien-3-yl]-(2-(1-pyrrolidinyl)-ethoxy phenyljketone which is available from Eli Lilly & Co. (LY 117018) , [6-hydroxy-2-(4-hydroxyphenyl)benzo (b) thien-3-yl] -(4-(2- (1-piperdinyl) ethoxy) phenyl] methanone, which is available from Eli Lilly £ Co. as the hydrogen chloride salt (LY156758) and raeso-3,4-bis (3 ’ -hydroxyphenyl) hexane as well as the dimethyl, dipropyl and 3'-acetoxy phenyl analogues which are described in U.S. Pat. No. 4,094,994 and a series of 1-phenyl-alkane and -alkenes, e.g. (E)-3-cyclopenty1-1-(4-hydroxyphenyl)-l~phenyl"l-butens and 2-cyclopentyl-l-[4-hydroxy~ or methoxyphenyl]-3-phenyl-2-propen-l-ol and EC-1157 which is available as the citrate salt frora Earraos Group, Ltd., Turku, Finland (see also Eur. Pat. Appln. EP. No 78,158). It is preferred to use an antiestrogen which shows minimal partial estrogen agonisra.
FC—1157, LY-117018, LY 156758 and Tamoxifen are at the preferred antiestrogens of the class of those possessing some agonistic activity.
Suitable antiestrogens which also include 7a-substituents of estradiol (European Pat. No. 0138504) and non-steroidal compounds bearing a similar aliphalie side-chain (U.S. Pat. 4732912) are represented by the general formula I: wherein the dotted lines represent optional double bonds; wherein Rt, R, and PL are independently selected from the group consisting of hydrogen, hydroxyl, alkylsulfonyl(lower)alkoxy, arylsulfonyl( lower) alkoxy, halogen, lower alkvl. lower alkoxy, lower alkysilyl, amino and nitro; wherein Ra is selected from the group consisting of hydrogen, hydroxyl, halogen, lower alkyl, methoxy, ethoxy, propoxy, hydroxyethoxy, lower alkoxy, acetoxy, propionyloxy, butyryloxy, oenanthoyloxy, cypionoyloxy. fcrans-4-n-butyl-cyclohexanecarbonoyloxy, (C3-C. 0) alkanoyloxy, lower alkoxy carbonyloxy,, carboxy, (C3-C.a)alkenoyloxy, (C3-C3a)alkynoyloxy or (C7-C10)aroyloxy; wherein Rs is selected from the group consisting of hydrogen, halogen, lower alkyl, amino and nitrile; wherein R, is in a position and is hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, lower alkylsilyl, amino, nitrile, nitre, nitroso, alkylsulf onyl, arylsulfonyl, lower alkylamino, diloweralkylamino s or is represented by the formulae AXR.x and A1-CY-A113^-X-R., wherein: A is straight- or branched-chain (C,-C3a) alkylene, (C.-CJa)alkenylene, (C.-Cse)alkynylene or fluoro-substituted analogs of the foregoing; u is an integer from 0 to 5; wherein A1 and A11 may be the same or different and are selected from the group consisting of a bond, straight- or branched-chain alkylene, straight- or branched-chain alkynylene, straight- or branched-chain alkenylene, and fluoro-substituted analogs of the foregoing, wherein A1 and A11 together have a total of from 3 to 30 carbon atoms, and Y is selected from the group consisting of -0-, -S-, -Se-, -SO-, -SO.-, -CO-, -MR..-, -SiR..R..-, -CRjjOR..-, -MR..CO-, -NR..CS-, -C0NR,.-, -CSMR..-, -C00-, -COS-, -SCO-, -CSS-, -SCS-, -0C0- and phenylene (R.. being hydrogen or lower alkyl); R,, is selected from the group consisting of hydrogen, straight- or branched-chain lower alkyl, lower alkenyl or lower alkynyl, (C3-C7)cycloalkyl, halogeno(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (Cd-C3 a)aryl„ (C.-C,,)arylalkyl. di(lower)alkylamino(lower)alkyl and fluoro26 substituted analogs of the foregoing, and wherein X is NR.
II -CONR,,-, -CSNR,,-, -NR.,CO-, -NR,,CS~, -NR,XONR,,-, -NR,,-C-NR.,-8 -SO.NR,,-, -CSS-, -SCS-, -NR.,-, -(N0)R23-, -(PGJR.,-, -NR„SCOO~, -NR,tSO3-, -S-, -SO- or -SO,-, (where K,3 is selected from the group consisting of hydrogen, lower alkyl,, and. a species which, together with R3l, forms a saturated or unsaturated heterocyclic ring having at least one nitrogen atom and, optionally, a second heteroatom selected from the group consisting of oxygen,, sulfur, silicon, selenium, nitrogen and fluoro-substituted analogs of the foregoing, and where R,4 is hydrogen or lowsr alkyl) wherein RjS is hydrogen, nitrile or nitro) (XR31 ©ay fora a tetrazole ring); wherein R., is selected from the group consisting off hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C.-C,θ)aryl, alkylsulfonyl, arylsulfonyl, a substituted 5- to 7-member heterocyclic ring having at least one heteroatcra (selected from oxygen, sulfur’, silicon, selenium, nitrogen), -(CH,)^ (wherein W is nitrile, hydroxyl, azido, nitroso, nitro, thionitrile, halogen, alkylsulfonyl or arylsulfonyl, and s is an integer from 1 to 6), GR2lJ (wherein R.e is hydrogen, lower alkyl or (C6~C, e)aryl) , DR,, (wherein D Is -Se-, ~NR„e, -8- or -0-, and R.. is hydrogen, lower alkyl), =0, -S, =Se, =NR,e (wherein R.a is hydrogen or lower alkyl;. wherein R,, and Rx, are independently hydrogen or lower alkyl; wherein R14 is selected from tha group consisting of hydrogen, hydroxyl, nitrile, nitro, nitroso, halogen, lower alkyl, lower alkoxy, lower alkyseleno, lower alkylamino or diloweralkylaraino; or R11) and R,s ; together are -CH,-, -CHX-, -CX,-, (X * halogen, carboxyl or alkoxycaroony1) , -0-, -S-, -Se-, >N-CN, >NR,s and >NCO.R1S wherern R,s is hydrogen or lower alkyl; - 27 ~ wherein Rxs is selected frcm the group consisting of hydrogen, hydroxyl, nitro, nitroso, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylseleno, lower alkylamino, di (lower) alkylamino, nitrile, azido, arylseleno, AXRJX, Αχ-[Y-Axx3^-X-R.x or Rxs and Rls together are -CH.-» -CHX-„ -CX.-S (X = halogen, carboxyl or alkoxycarbonyl)» -0-, -S-, -Se-,, >N-CH, >NR3S and >NCQ,R,„ wherein RJS is hydrogen or lower alkyl; wherein Ris is selected from the group consisting of hydrogen, nitroso, halogen, lower alkyl, carboxyl, lower alkoxy, lower alkylseleno, lower alkylamino, nitrile, azido, arylseleno, lower alkylseleno, di (lower) alkylamino, AXR,x, or AHY-A^l^X-R.. f wherein ^n(c) selected from the group consisting of hydrogen, hydroxyl, lower alkyl, halogeno (lower)alkyl, AXR3 , ΑΧ-[Υ-Α1Χ]^Χ-Κ1Χ, Bl-T-R, „ wherein: Sx is straight- or branched-chain (Cx-Cχ,) alkylene , (C.-CXJ) alkynylene, (C3-Cx,) alkenylene; T is -0-, -HR3.X, -Se-» -S- or S-S and Rse and R,, are independently hydrogen, lower alkyl, or RJ0 and R3, , together are (C3-C7) cycloalkyl» (Cs-C,)cycloalkenyl, (C3-C,)eycloalkyl or (C3-C7) cycloalkenyl having one or more hydrogen atoms replaced by halogen atoms, -HOCHR3, and -CeCR33 wherein: R3j- and R33 are independently hydrogen, halogen, tri(lower)alkylsilyl, carboxyl, carbonyl, lower alkoxy, nitrile, sulfinyl lower alkyl, AXR,,„ A1-[Y-Alx]^-X-R,χ or a species represented by the formula: n -HC Q 2)n wherein n and ra. are independently Q to 6 and Q is -Se-, -SiKx-, —S~, "0 or -NR3Jk- wherein R31 is hydrogen, lower alkyl or (C,~C.)alkanoyl; or a species represented by the formula: wherein q is -CH.-, -S-, -O- or -NR3S- wherein R., is hydrogen or lower alkyl; wherein R, 7^j is preferably selected from the group consisting of hydrogen, hydroxyl, halogen, alkoxy, (Ct"C7)alkanoyloxy, (C3-C.)alkenoyloxy, (C3-CT)alkynoyloxy, cycloalkenyloxy, 1-alkyloxy-alkyloxy, 1-alkyloxy eycloalkyloxy, alkylsilylaxy and a divalent conrnan species formed jointly by R1T and R1T^j , said divalent eoasnon species being selected from the group consisting of <1 -S, or -"MOR3a wherein RJ6 is hydrogen or lower alkyl.
An. alternative antiestrogen may be represented by the general formula II: where the dotted lines represent sn optional double bond of Z or Ξ configuration; wherein Rt, , Rfc s, Ru , and Rs. are independently selected from the group consisting of hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, alkylsulfonyl lower alkoxy, arylsulfonyl lower alkoxy, lower alkylsilyl, amino, nitro, nitrile and nitroso. wherein RWJ, R4Jk, R4S and Rs, are independently selected from the group consisting of hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, alkylsulfonyl lower alkoxy, arylsulfonyl lower alkoxy, lower alkylsilyl, amino, nitrile, nitro, nitroso, azido, lower alkylamino, dilower alkylamino, AXR,x, Y4T-A* [Y-A*) -X-R3x, -X-R,x wherein: A, A1, A11, X, Y and u are defined as previously in fotmule I, and Y*. is absent or is selected from the group consisting of carbonyl and carboxyl; wherein Rt, and R are independently selected from the group consisting of hydrogen, hydroxyl, halogen, lowar alkyl, methoxy, ethoxy, propoxy, hydraxye thoxy, lower alkoxy, lower alkoxy carbonyloxy, carboxyl, acetoxy propionyloxy, butyryloxy, oenanthoylosy, cypionoyloxy, trans-4-n-butylcyclohexanecarbonoyloxy, (Cx-C.e) alkanoyloxy, (C3"C.e) alkenoyloxy, (C3-C,e) alkynoyloxy, (CT-C1X) aroyloxy and alkylsilyloxy; wherein. Rs6 and R^. are independently selected frora the group consisting of hydrogen, amino, lower alkylamino, dilower alkyl amino, nitro, nitrile, nitroso, halogen, lower alkyl, lower alkenyl, lower alkynyl, o lower alkyl, halogeno lower alkenyl, halogeno lower alkynyl, alkyl sulfonyl, aryl sulfonyl, a substituted 5- to 7-member heterocyclic ring having at least one heteroatora (selected frora oxygen, sulfur, silicon, selenium, nitrogen), -(CH ) V (wherein V is nitrile, hydroxyl, * s azido, nitroso, alkoxy, nitro, thionitrile, halogen, alkyl sulfonyl or aryl sulfonyl and s is an integer frora 1 to 6) , a moiety of the formula: ‘61 wherain: F is absent or selected from the group consisting of alkyl, carbonyl or carboxyl, wherein the phenyl ring say be halogenated, wherein Rsl is selected from the group consisting of hydrogen, hydroxyl, halogen, lower alkyls * lower alkenyl, lower alkynyl, nitrile, nitro, nitroso'or X4t(CH3) Yft„ (Xfce being selected from tha group consisting of -0-, -S~, -Se-, -SO™, ~SQa~ and -CO-, and Y,ifi being selected from the group consisting of hydroxyl, amino, monoalkyl amino, dialkyl amino, dimethyl N-axide, N-aziridyl, guanidino, N-pyrrolidino, N-piperidino, N-methylpiperazino, N-morpholino and alkoxy, and n being an integer from 1 to 6) , AXR3, , Yl ?-A1-(Y-Al x3u"X"R2, A — [Y-A1 nu-X-Rj, Wherein A, A3·, A31, X, Y, Yti are defined previously for Rk., Rtfc, R^ and Rsi; a species which in combination with another substituent from formula II, forms a moiety selected from the group consisting of -CH,-, -CBX-, -CX.(X being, halogen, carboxyl or alkoxycarbonyl), -O-, -S-, -Se-, >N-CN. >MRjS and >NC0.R3S (R39 being hydrogen or lower alkyl), lower alkylene, ~(CH,) OCCH.) -, ~(CH.)J>(CHS) -, -(CH2) Se(CH5) -, -(CHJJJOCCH.) - (CH a )rS03 (CH,)s- , - (CH,)^CQ(CH.)g„ - (CH.)rNR., (CH.)g-, -(CH.)^SiR.3R33(CH.)s- and ~(CH.) /ZR. ,QR2. (CHJ s~ (wherein R33 being hydrogen or lower alkyl, r and s being independent integers from 0 to 3); a moiety of the formula: »» flA"CY-R*A]u-XR21 .(rv ) 3 t V&A 1 wne^sm: Z is absent ar is selected frcm the group consisting es lover alkvlene. halogeno lover alkylene.-(CH„J Q~. -(CH.) S~„ ‘ ό H 9 u -(CH.)nSe-, -(CHJ^SO-, -(CH,)^SO.-B -(CH.?nCCH„ -(CSJ^NR.
LA &A W ®* and -(CH,) CR.„QR„,-, n being an integer ire» Aa 3» and R.. being selected fro» a group consisting os hydrogen, hydroxyl, halogen, lower alkyl, lover alkoxy and lover alkylsil; u * * wherein: N is nitrogen aces and A1» Τ» AXi, u„ X and Rzl are defined as previously.
The inhibitors of sex steroid biosynthesis found useful in the present invention include ’ those ccaoaunds which inhibit biosynthesis of sex stsroids from precursor steroids of adrenal and/or ovarian origia(s) preferably of bath ovarian and adrenal origin. Their action can also be exerted in the peripheral tissues, especially in the breast and the «nde~ metrics.
The inhibitor of sex steroid formation may be an inhibitor of aromatase activity (4-OH-androstanedione and FCS 34304, as examples) or of 36-hydroxystaroid, δ5~δ4~isomerase activity such as Trilostane, Epostane or 4-MA, as examples. Of particular interest, 1 β-methylene estrone and 16-methylene estradiol act as specific inhibitors of 17β-estradiol dehydrogenase (Thomas et al,, J. Biol.
Chem. 258: 11500-11504, 1983.
Referring to synthesis scheme X below, a preferred antiestrogen TO which may also act as an inhibitor of sex hormone formation (e.g. inhibitor of estrogen formation) may be prepared as follow: N-butyl, N-methyl-11-(16 -chloro-3', 17'f3~dihydroxy-estra-1', 3', 5' (10')-trien-7'a-yl) undecanaraide (EM 139. Scheme 1) N-butyl, N-methyl-11~(3',17'-diacetoxy-estra-1',3',5'(10'), 16' — tetrasn-7'a~yl) undecanamide (3) To 11-(3-bensoyloxy-17-oxo~estra-1,3,5(10)-trien-7a-vl) undecanoic acid (1) (3.94 g, 7.22 mmol), prepared as described (Bucourt et al., J. Biol. Chem. 253: 8221-8228, 1978), dissolved in anhydrous CK2CL9 (1θθ ml) and cooled at -10’C was added tributylamine (2.18 ml, 9.15 nmol) and isobutylchloroformate (1.30 ml, 10.0 mmol). The solution was stirred during 35 rain, and N-methylbutylamine (13 ml, 109.7 mmol) was added. The mixture was warmed co room temperature and stirred during 1 h. Afterward, CH.CI, was added and the organic phase was washed with IN HCl, water, saturated sodium bicarbonate solution and finally with water, dried with anhydrous MgSO, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel. Elution with mixture of EtOAc/hexane (1.5:8.5 v/v) yielded N-butyl, N-methyl-ll-(3'-benzoyloxy17'-oxo-estra-1',3 ' ,5'(10')-trien-7’u-yl) undecanamide (4.25 g, 96%) as colorless oil; IR υ (neat) 1750» 1725 and 1640 es-1. The above described, benzoyloxy amide (341 mg, 0.54 saaol) was dissolved in methanol (10 ml) and cooled at 0°C. Following this 2N NaOH (5 ml) was added and the mixture was stirred during 60 min. at QeC. The solution was neutralized with IN HCl and extracted with CH.C1.. The organic phase was dried with anhydrous hgSO,. and che solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel. Elution with mixture of EtOAc/hexane (3:7 v/v) yielded N-butyl, N-methyl-11-(3'-hydroxy-17'-oxoestra-1’ ,3’ ,4' (10)-trien-7'G-yl) unaecanamide (2) (284 mg, 97%) as colorless oil; lH-NMR o (CDClj 0.91 (s,3H,18'-CHJ , 2.76 app (d, 1HJ=16,3Hr, part of ASX system, 6’-H) 2.96 and 2.98 (2s,3H N-CHJ , 3.27 and 3.38 (2t , 2H.J=7.5Hz,N-CH.-), 6.63 (broad s.lH,4'-H) . 6.70 (broad d,1H,J= app 8.5 Kz,2’-H), 7.12 (d,lH,J=8.4 Hz,l'-H); IR u (neat) 3270, 1730, 1615 cm-3; MS m/e 523 (M,10Q%), 508 (M—CH3,32%) , 142 (C.HSCON(CH JCtH/, 47%). The ketone amide 2 (163 mg, 0.50 mmol) was dissolved in isoprenyl acetate (10 ml). p-Toluenesulfonic acid (44 mg) was then added and the solution was distilled to about two-thirds of the original volume in 7 hrs and was then stirred at reflux for 12 hrs. Afterwards, the solution was cooled with an ice-water bath and extracted with 50 sal of cooled ether. The ether was washed with a cooled satured sodium bicarbonate and water. Ihe organic phase was dried with anhydrous MgSOt and ch® solvent was removed under reduced pressure. The residue was filtered through alumina (15m x 50 m alumina Woehha neutral, activity ll) using a mixture of benzene-diethyl ether (3:7 v/v) as eluant. The solvent was removed under reduced pressure and. the residue was purified by flash chromatography on silica gel. Elution, with mixture of EtOAc/hexane (1:4 v/v) yielded the N-butyl» N-methyl-11- (3',17' -diacetoxy-estra- 1s , 3' »5 * (10f)» lo'-tetraen-7'c-yi) undecanaari.de (3) (244 mg, 80S) as colorless oil; x5NMR o (CDClj) 0.92 (sS3H,18·-CH3), 0,92 and 0.95 (2t,3H,1=7.0 Hz»N(CH3)3CH3) p 2.18 (s ,3H, 17’-OCQCH3) » 2.28(s ,3H»3 OCOCH,,) , 2.76 app (d, 1HV1=16.1 Hz. part of ABX system,S5-Η), 2.90 and 2.96 (2s„3E,N-CK3), 3.26 and 3.35 (2t ,2H,J=7.6 Hz,N-CH,-) , 5.52 (m,1H,16’-H), 6.SO (broad apo * s»IH,4'-H) , 6.85 (dcLlH»J,=9.1 Hz and 1,=3.0 Kz,2'-K).» 7.27 (d?lHtJ=9.l Ηζ,Ι'-H); IE v (neat) 1750, 1635» 1200 cmr-*; MS m/e 607 (M‘,2%), 565 (M’-CQCH.,100%), 550 (M*-C0CH.~CH3,13%)» 523 3 ,45%) , 142 (C2H^CaN(CH3)C4Ha-,55%) , 129 (CfcH9(CH3)NCQCH3»38%)„ 114 (G,H9(CH3)NCCT 860%) , 86 (C,HS (CH3)N\2S%); EXACT MASS calcd for C3,KS7OSK 607.4239, found 607.4234.
The Η-butyl» N-methyl-11-(16's-chloro-3’acetoxy-17s~oxQ-estra~l’,3',4' (10' )-triene-7 'e-yl) undecananri.de (4) To diacetate amide 3., dissolved in 5 ml of acetone„ was added a solution of sodium acetate (2.6 equivalents) in acetic acid and water (1:11.3 v/v) and then, was treated with tertbutyl hypochlorite (1 eq.) : prepared from t-butanol (4 ml) and lavel water (Javex 6.1%. 50 ml), uie clear solution was warmed to 55®C and stirred tor 1 h. Afterwards, the solvent was evaporated to dryness. The residue was dissolved in ether (100 ml) and water was added (20 ml). The organic phase was washed with water, dried with anhydrous MgSCL and evaporated to dryness. The residue was purified by chromatography on silica gel carried out with mixture of EtOAc/hexane (3:7 v/v) to give the N-butyl, N-methyl-ll-(16'a-chloro3 'acetoxy-17'-oxo-estra-l8,3 1 ,4’ (10' )-trien-7’c-yl) imdecanaaide (4) (115 mg, 89%) as colorless oil; 3K-NMR.6 (CDC13) 0.92 and 0.95 (2t,3E,J~7.0 Hz,N(CH.)3CH3) , 0.96 (s ,3H, 18 *-CHs) , 2.28 (s,3H,3 ’~OCOCH3) , 2.80 app (d,lH,J=16,6 Hz, part of ABX system, 6S~H) 2.90 and 2.96 (2s,3H,N-CHa), 10 3.24 and 3.35 (2t ,2H,J«7.4 Hz,-N-CH.-), 4.46 (d,lH,J=6.6 Ηζ.16'β-Η), aPP 6.82 (broad s,lK,4'-K), 6.86 (dd,lH,J»9.1Hz and Js^,2.6Hz,2s-H), 7.29 (d,lH,J=9.1 Hz.l'-H); IR (neat) 1750, 1640, 1205 aa-3; MS m/e 601, 599 (M’,24%, 68%), 142 (C3H.CON(CK3)C.H/, 100%), 114 (C,HS (CH3)NCCT ,93%).
N-butyl, N-methyl-ll-(16a-chloro-3’,17'β-dihydroxy-estra-l’,3',5’(10')trien-7'c-yl) undecanamide (EM 139) A stirred solution of haloketone amide 4 in anhydrous tetrahydrofuran (THF) (10 ml) under argon was chilled to -70eC with 2-propanol/dry ice 2θ bath to -70"C with 2-propanol/dry ice bath. A solution of 1.0 M of lithium aluminium hybrids (2 eq.) was then added dropwise. After 30 min, the reaction was allowed to return slowly at 0°C for 5 min, then vas quenched by the dropwise addition of a mixture of THF-EtOAc (5 ml) (1:1 v/v) and acidified at pH v 4 with (10%) HC1. The mixture was stirring for Sc min. at room temperature and then extracted with EtOAc. The organic phase was washed with water, dried on anhydrous Na3S0k and evaporated under reduced pressure. The residue included two important antiestrogens which were separated by chromatography on silica gel and eluted with a mixture of EtOAc/hexane (4:6 v/v): N-butyl, N-methyl-11-( 16’a-chloro-3'17'a-dihydroxy-estra-l' ,3’ ,5' (101 )trien-7’c-yl) undecanamide (EM 170) (15 mg, 29%) as colorless oil; analytical sample was obtained by HPLC purification; ’H-BMB, δ (CDC13 „ 400 MHz) 0.79 (s,3H,18'-CHj , 0.93 and 0.96 (2t, 3H,J=7.3 Hz,N(CH J SCH J , 2.80 (2H,JS ,g=17.1 Hz and J6>7 - 4.5 Hz, Δδ-24.34 (Hz, system ABX, 6'H), 2.94 and 2.99 (2s, 3H.N-CHJ , 3.25 (dd,J, = 7.6 Hz and Js - 7.4 Hz) and 3.32-3.43 (ra)-[2H,-N-CH.-] , 3.71 Cd„lH,J=4.5 Ηζ,17'β-2), 4.63 (ddd, IH. JX6,XS ’« 10.2 Hz, JX8?,7 "4.5 Hz and Jxeus 3.9 Hz, 16’β-Η), 6.50 (d, IH, J=24 Hz, 3’-QH), 6.60 (d, 1H,J=2.5 Hz, 4'-H), 6.66 (dd,lH,Jx=8.4 Hz and J3=2.5 Hz, 25-H), 7.14 (d,lH,J«8.5 Hz, 1'-H); IR u (neat) 3300, 1615, 1495 cm1; MS m/e 561,559 (M‘, 40%, 100%), 523 (M’-HCl, 20%), 142 (C.HXONfCHJC.H j, 44%), 114 (CAHB (CH JCN0‘, 37%); Exact mass calculated for C34H3403N33C1 559.3785, found 559.3821; - and -N-butyl, N-methyl-11-( 16’a-chlaro-3’ , 17’3-dihydro2ty—estra-1’3’ ,5' (10')trien-7'α-yl) undecanamide (EM 139) (25 mg, 55%) as a colorless oil; analytical sample was obtained by HPLC purification; 1H-NMR δ (CDC13, 400 MHz), 0.81 (s,3H, 18'-CHJ , 0.93 and 0.96 (2t, 3H,3*7.3 Hz, (CHJ3CHJ, 2.78 (2H, Je>(i = 16.2 Hz and Js,,»4.5 Hz, Δ3-24.34 Hz, system ABX, 6'-H) , 2.94 and 2.99 (2s, 3H,N-CHJ , 3.27 (dd, J,-7.6 Hz and 3,-7.5 Hz) and 3.31-3.45 (M)[2H, -N-CH.-], 3.86 (dd, IH , Jx7,, .-^,=3.4 Hz and J,.,, g =5.9 Hz, 17'g-H), 4.11 (ddd, IH, Jxe,xs =10.8 Hz, J14,17=5.9 Hz and ~ 37 Jle,ls=2.5 Zz, 16'β-Η), 6.56 Cd, 1H, 1=19.7 Hz, 3’-0H), 6.61 Cd, 1H, 1=2.5 Kz, 4'-H), 6.66 (dd, IK, 1,.=8.4 Zz and 1,=2.6 Zz, 2’~K) , 7.13 (d, 1H, 1-8.4 Hz, l’-H); IR υ (neat) 3320, 1615, 1490 ca"1; MS m/e 561,559 CM’, 38%, 100%), 523 (M’-HCl, 16%), 142 (C.H^COK(CH.) CAH, \ 80%), 114 (C.Hg(CH3)MCO",76%); Exact mass calculated for C3.Hs.O,N3SC1 559.3785, found 559.3825..
Sch ®5WflR X Eh 170s R"(CH,),«CGN(CH3)CtH,, R,»H, R,»QH & tat * i · fe ’ E, Eh 139: RaCCHjJjQtOHCCHjK^H,, RjsGH, Rg=H A preferred inhibitor of Up-estradiol dehydrogenase possesses noreover an antiestrogenic activity and is represented, for example, by the compound of the formula III: wherein K,3 is selected from the group consisting of hydroxyl, halogen» lower alkoxy, methoxy, ethoxy, propoxy, hydroxye thoxy, (C3-C., e) alkanoyloxy, acetoxy, pronionyloxy 8 butyryloxy» oenaixthoyloxy» cypionoy loxy» trans-4-n-butyl-cyclohexanecarbonoyloxy, lower alkoxy carbonyloxy, 5 carboxy, (C3-CS0) alkenoyloxy, (C3-C30) alkynoyloxy, (C?-CXo)aroyloxy; wherein R1T^jis selected from the group consisting of hydrogen and hydroacyl; wherein &ιβ(α) *·* & halogen, preferably chlorine, fluorine, or bromine; i·5 preferably hydrogen, or and Rx g together fora =GG2; wherein G.' is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl. nitrile, alkoxycarbonyl, alkylcarbonyl and carboxyl; wherein RX7^j is selected from the group consisting of hydrogen, hydroxyl, (CX~C7) alkanoyloxy, (C3-CT) alkenoyloxy, CG,-G7) alkynoyloxy, !5 cycloalkenyloxy, 1-alkyloxy-alkyloxy, 1-alkyloxy cycloalkylcxy, alkylsilyloxy and a divalent common species formed jointly by Rx7^j and sa^°· divalent common species being selected from the group consisting of -Qp -S, NR5S or NQRje, wherein R, s is hydrogen or lower alkyl; wherein A1, A’·1, Y, X, R. x and u are defined previously in the formula I; And/or by 16,17-secosteroid derivative of the molecular formula; wherein the dotted lines represent optional double bonds, wherein the A-ring is optionally aromatic; wherein Rx, R, and Rk are independently selected from the group consisting of hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, lower alkylsilyl, amino and nitro; wherein R3 is selected from the group consisting of hydroxyl, halogen, lower alkoxy, (G,-C,0)alkanoyloxy. (C3~C,0)alkenoyloxy, (C3-C,e)alkynoyloxy, (C.-C,e)aroyloxy„ lower alkoxycarbonyloxy or a divalent common species formed jointly by R3^and R3 said divalent common species being selected from the group consisting of ~-O, =S, =NR36 or ~MGR3S wherein R3g is hydrogen or lower alkyl; wherein Rs and R,Q are absent or selected from the group consisting of hydrogen or lower alkyl; wherein Rs Is selected from the group consisting of hydrogen, halogen, · lower alkyl, amino or nitrile; wherein ?.lx is selected from the group consisting of hydrogen, lower alkyl, lower alkynyl, (Cg-Cx0)aryl, a substituted 5- to 7-member heterocyclic ring having at least an heteroatcm (selected from oxygen, sulfur, silicon, selenium and nitrogen)„ (CH„) W (wherein W Is nitrile, hydroxyl, azido, nitroso, nitro, thionitrile, halogen, alkylsulfonyl or arylsulfonyl, and s is an integer from 1 to 6), OR,5 (wherein Rss is hydrogen, lower alkyl or (Ce~Gle)aryl), DR,» (wherein D is -Se-, -NR,6-, - S- or -0-, and R,» is hydrogen or lower alkyl), =0, S, -Se, =NR, „ and =NOR3 (wherein R,e is hydrogen or lower alkyl); wherein R13 and R33^j are hydrogen'or lower alkyl; wherein Ρ·.,3^ is selected from the group consisting of 1-oxo-2-propynyl, l-hydroxy-2-propynyl, carboxyl, alkoxycarbonyl and alkylcarbonyl; wherein and Rlfc^^ are selected from the group consisting of hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl and halogeno analogs of the foregoing; wherein A1, AXi, Y, n, X, R., are defined as previously in the fonanla 1.
A preferred inhibitor of prolactin secretion is brcanocryptine, e.g. Parlodel (available from Sandoz, Bale, Switzerland). A preferred inhibitor of growth hormone secretion is a somatostatin analogue, e.g. Sandostatir. (available from Sandoz, Bale, Switzerland). A preferred inhibitor of ACTS secretion is hydrocortisone acetate, e.g. Solucortef (available from Upjohn).
In this invention, the LHRH agonist or antagonist, antiestrogen, androgen, and, where applicable, the progestin, the inhibitor of steroid biosynthesis (hydrocortisone) and the inhibitor of prolactin and/or growth hormone and/or AGTH secretion are administered as pharmaceutical compositions via topical, parenteral or oral means. The LHRH agonist or antagonist is administered parenterally, i.e., intramuscularly, subcutaneously or intravenously by injection or infusion by nasal drops or by suppository, where applicable intra-vaginally. The LHRH agonist or antagonist may also be microencapsulated in or attached to a biocompatable, biodegradable polymer, e.g., poly(d,l-lactide-co~glycolide) and subcutaneously or intramuscularly injected by a technique called subcutaneous or intrasmuscular depot to provide continuous, slow release of the LKRH agonist or antagonist over a period of 30 days or longer. Tne most preferred route of administration of the LHRH agonist or antagonist is subcutaneous depot injection. Preferably the antiestrogen will be administered oral41 ly. Preferably, the inhibitors of sex steroid biosynthesis such as aminoglutethimide and ketoconazole, the androgen and progestin, as veil as the inhibitor of prolactin, growth hormone and ACTH secretion, when used, are administered orally. The antiestrogen, androgen, progestin and inhibitor of sex steroid formation can also be administered in a slow release formulation, e.g. poly(d.l-lactide-coglycolide) or as implants.
The amount of each component administered is determined by the attending clinicians taking into consideration the etiology and severity of the disease, the patient's condition and age, the potency of each component and other factors. In the combination therapy of breast and endometrial cancer, according to this invention, the following dosage ranges are suitable.
Tne LHRH agonist or antagonist is generally administered at from about 10 to 5000 pg per day with contemplated dosage ranges of about 10 to 1500 pg per day and about 250 (preferably 200 pg to 500 pg per day) for the LHRH agonist and to about 50 to 5000 pg per day for the LHRH antagonist being preferred.
In the most preferred embodiment of this invention, the LHRH agonist or antagonist is administered subcutaneously in a daily dose of 500 pg 2θ for the first 30 days and thereafter subcutaneously in a daily dose of 250 pg regardless of the patients' body weight. When the LHRH agonist cr antagonist is administered, once every 30-day period is used, with a dose of 750 to 15,000 pg per 30**day period being preferred. Similar daily delivery doses are used for longer-term controlled release formulations.
The androgen and progestin compositions are generally administered in a dosage range of about 0.10 to 40 ag/kg (body weight) per day with 45 rag per day in three equally divided doses being preferred.
The aminoglutethimide compositions (when used) are, administered initially in a dosage of 250 mg given at 8-hour intervals and the dosage may be increased in increments of 250 mg daily up to a total daily dose of 2 grass.
The ketoconazole compositions (when used) ase administered orally in a dose of 250 mg given at 8-hour intervals and may be increased to a daily dose of 2 grams.
Other inhibitors of sex steroid biosynthesis are preferably administered in dosages ranging from about 0.1 to 40 mg/kg per day with 45 mg per day in three equally divided doses being preferred.
The antiestrogen compositions are administered in a dosage range of about 0.05 to 25 mg/kg body weight per day, with 10 mg, especially 20 mg, in two equally divided doses being preferred.
The inhibitor of prolactin secretion, bromocriptine. being the example, Is administered at the dose of 2 mg once or twice daily. The inhibitor of growth hormone secretion, the somatostatin analog, sandastatin, being an example, is administered subcutaneously at the dose of 100 to 1000 pg per day in these equally divided doses.
The glucocorticoid (also inhibitor of ACTH secretion)» especially hydrocortisone compositions (when used) , are administered orally in a dosage range of about 0.1 to 20 mg/kg body weight per day. Preferably, the hydrocortisone is administered orally at the dose of about 10 mg in the morning and about 5 rag doses in the afternoon and In the evening.
The LHRH agonist or antagonist, antiestrogen, androgen, progestin and inhibitor of sex steroid biosynthesis as well as the inhibitor of prolactin, growth hormone and ACTH secretion each may be administered i separately or when the modes of administration are the same, all or at least two of them may be administered in the same composition, but xn any case the preferred ratio of LHRH agonist to antiestrogen, to androgen (when used) , to progestin (when used) , to inhibitor of sex steroid biosynthesis (when used) administered daily will be about 250 pg of LHRH agonist to about 45 mg of androgen, about 45 mg of progestin, about 15 mg, of antiestrogen, to about 45 mg of inhibitor of sex steroid biosynthesis at about 750 mg of inhibitor of adrenal steroid, secretion.
Xn the therapy of breast and endometrial cancer, combining the administration of an LHRH agonist or antagonist, sn antiestrogen, an androgen, and a progestin, the dosages preferable are as follows: the LHRH agonist or antagonist is generally administered at from about 10 to 2000 pg per day, with contemplated dosage ranges of 10 to 500 pg per day, 50-250 pg per day and 250 to 500 pg per day being preferred. In the most preferred embodiment of this aspect of this invention, the LHRH agonist or antagonist is administered subcutaneously iii a daily dose of 500 pg for the first 30 days and thereafter subcutaneously in a daily dose of 250 pg regardless of the patients' body weight. When the LHRH agonist or antagonist is administered, once every 30-day period, by intramuscular or subcutaneous depot injection, a dose from about 300 to 60000 (occasionally 15000) pg per 30-day period is used, with a dose of 750 to 6000 pg per 30-day period being preferred. The androgen and progestin compositions are generally administered in a dosage range of about 0.10 to 40 mg/kg (body weight) per day with 45 especially 75 mg per day in three equally divided doses being preferred. The antiestrogen and inhibitor of sex steroid formation compositions are administered in a dosage range of about 0.1 to 25 mg/kg body weight per day, with 10 mg in three, preferably with mg in two, equally divided doses being preferred. The arainoglutethimide compositions when used are administered initially in a dosage of 250 mg given at preferably 8-hour intervals and the dosage may be increased in increments of 250 mg daily up to a total dose of 2 grams. The ketoconazole compositions when used are administered orally in a dose of 250 mg twice daily and may ba increased to 200 mg, four times a day.
The LHRH agonist or antagonist, antiestrogen, androgen, progestin and inhibitor of sex steroid formation, each may be administered separately or when the modes of administration are the same, all or two or three of them aay be administered in tile same composition, but in any case the preferred ratio of LHRH agonist to androgen (or progestin) to antiestrogen administered daily will be about 250 p.g of LHRH agonist to about 45 mg of androgen and progestin to preferably 20 mg of antiestrogen.
In the therapy of breast and endometrial cancer, it is preferred that the LHRH agonist is [D-Trp^, des-Gly-NHj^LHRH ethylamide be administered subcutaneously in single daily dose of 500 pg for the first thirty (30) days of treatment and thereafter in a single daily dose of 25 p.g; the androgen is MPA which is administered orally in three equally divided daily doses of 15 mg each; and the inhibitor of sex steroid biosynthesis is ketoconazole and/or aminoglutethimide, each of which is administered orally in three equally divided doses of 250 mg every 8 hours; and the hydrocortisone (if used) is administered orally at a dose of about 10 mg ia the morning and two equally divided doses of about 5 mg, 8 and 16 hours thereafter; and the antiestrogen is (2)-2-(4-(1,2dipheny1-1-butenyl)phenoxy1]-n,N-dimethylethylamine (Tamoxifen) which is administered orally in two equally divided doses of about 10 mg every 12 hours.
In the combination therapy of breast and endometrial cancer administration of the antiestrogen, androgen, progestin, inhibitor(s) of steroid biosynthesis, glucocorticoid and LHRK agonist or LHRH antagonist can be started in any order of sequence. Preferably, the administration of the androgen and antiestrogen is started before (preferably two to four hours before) the administration of the LHRH agonist or LHRH antagonist is started. Preferably, the acrainistra5 tion of the inhibitor(s) of sex steroid biosynthesis is started on the same day as the administration of the LHRH agonist or LHRH antagonist. However, the attending clinician may elect to start administration of the LHRH agonist or antagonist simultaneously with the androgen, progestin and inhibitor of sex steroid formation.
When patients whose ovaries have already bean surgically removed are treated according to this invention, the administration and dosage of the androgen and the other components of the therapy (except the LHRH agonist or antagonist which is not used) are the same as indicated for the therapy in which the LHRH agonist or antagonist is used.
The LHRH agonists or antagonists useful in the present invention are typically amorphous solids which are freely soluble in water or dilute acids, e.g.» HCl, H3S04, citric, acetic, mandelic or fumaric. The LHRH agonist or antagonist for subcutaneous injection is supplied In vials containing 5 ml of sterile solution with the LHRH agonist or antagonist at a concentration of about 1.0 mg/ml.
A typical pharmaceutical composition of the LHRH agonist or antagonist includes the LHRH agonist or antagonist or a pharmaceutically acceptable acid salt thereof, benzyl alcohol, a phosphate buffer (pH 6.0-6.5) and sterile water.
The LHRH agonist or antagonist for intramuscular or subcutaneous depot injection may be microencapsulated in a biocompatible, biodegradable polymer, e.g.» poly (d,l-lactide-co-glycolide) by a phase separation process or formed into a pellet. The microspheres may then be suspended in a carrier to provide an injectable preparation or the depot may be injected in the form of a pellet. See also European patent application EPA No. 58,481 published Aug. 25, 1982 for solid compositions for subdermal injection or implantation or liquid formulations for intramuscular or subcutaneous injections containing biocompatible, biodegradable polymers such as lactide-glycolide copolymer and an LHHH agonist, e.g. D-Ser"tBuO®, Azgly-®-LHRH. These formulations permit controlled release of the peptide.
The inhibitors of sex steroid biosynthesis, e.g.» aminoglutethimide and ketoeenazole and the glucocorticoid, e.g.» hydrocortisone (when used) are typically compounded in customary ways for oral administration, e.g., in tablets, capsules and the like.
The androgen and progestin useful in the present invention are typically formulated with conventional pharmaceutical excipients, e.g.» spray dried lactose and magnesium stearate into tablets or capsules for oral administration. The antiestrogens, when used with the invention, are typically compounded in customary ways for oral administration, e.g.» in capsules, tablets, as dragees or even in liquid form, e.g., suspensions or syrup’s. One or more of the active substances, with or without addiθ tional types of active agents, ean be worked into tablets or dragee cores by being mixed with solid, pulverulent carrier substances, such as sodium citrate, calcium carbonate or dicalcium phosphate, and, binders such as polyvinyl pyrrolidone, gelatin or cellulose derivatives, possibly by adding also lubricants such as magnesium stearate, sodium lauryl sulfate, Carbowax or polyethylene glycols. Of course, taste-improving substances can be added in the case of oral administration forms.
The therapeutically active antiestrogen compound should be present in a concentration of about 0.5-90% by weight of the total mixture, i.e.. in amounts that are sufficient for maintaining the above-mentioned dosage range.
As further forms, one can use plug capsules, e.g., of hard gelatin, as well as closed soft-gelatin capsules comprising a softener or plasticiser, e.g. glycerine. The plug capsules contain the active substance preferably in the form of granulate, e.g., in mixture with fillers, such as lactose, saccharose, mannitol, starches, such as potato starch or amylopectin, cellulose derivatives or highly-dispersed silicic acids. In soft-gelatin capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as vegetable oils or liquid polyethylene glycols.
In place of oral administration, the active compounds may be administered parenterally. In such case, one can use a solution of the active substance, e.g., in sesame oil or olive oil. One or more of the active substances (androgen, antiestrogen, progestin and/or inhibitor of sex steroid formation) can be microencapsulated in or attached to a biocompatible, biodegradable polymer, e.g. poly(d,llactide-co-glycolide) and subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of 2 weeks or longer.
The invention provides kits or single packages combining the pharmaceutical compositions useful for the combination treatment of breast and endometrial cancer as discussed above. The kits and packages may also contain instructions to use the pharmaceutical compositions in accordance with the present invention. This aspect s of the invention is exemplified by the following discussions: for - 48 the treatment of breast or endometrial cancer, a four-component kit provides an antiestrogen, an androgen and an inhibitor of sax steroid formation oral pharmaceutical compositions and a LHRK agonist or LHRH antagonist parenteral composition while a three-component kit could be an antiestrogen, an androgen oral pharmaceutical composition or the oral compositions of an antiestrogen and an inhibitor of sex steroid biosynthesis with the LHRH agonist or LHRH antagonist parenteral composition.
Following the above treatment using the described regimen, tumor growth and bona metastases of breast and endometrial cancer are inhibited and in some instances complete remission may occur.
The terms and descriptions used herein are preferred embodiments set forth by way of illustration only, and are not intended as limitations on the many variations which those of skill ia the art will recognize to be possible in practicing th® present invention as defined by the following claims.

Claims (10)

CLA1MS
1. A kit for treatment of breast or endometrial cancer, said kit including a pharmaceutical composition comprising an antiestrogen and at least one pharmaceutical composition selected from the group consisting of a pharmaceutical composition comprising an inhibitor of sex steroid formation chosen from the group consisting of an inhibitor of aromotase, an inhibitor of 30 - hydroxysteroid δ 5 ~δ*-isomerase and an inhibitor of 170 - estradiol dehydrogenase, a pharmaceutical composition comprising an inhibitor of ACTH secretion and a pharmaceutical composition comprising an inhibitor of growth hormone secretion.
2. A kit for treatment of breast or endometrial cancer, said kit including a pharmaceutical composition comprising an inhibitor of ovarian hormonal secretions, a pharmaceutical composition comprising an antiestrogen, and at least one pharmaceutical composition comprising a compound selected from the group consisting of a pharmaceutical composition comprising an inhibitor of sex steroid formation chosen from the group consisting of an inhibitor of aromotase, an inhibitor of 30 hydroxysteroid δ 5 -δ 4 -isomerase and an inhibitor of 170 - estradiol dehydrogenase, an androgenic compound, an inhibitor of growth hormone secretion and an inhibitor of ACTH secretion.
3. A kit according to Claim 1 or Claim 2, wherein said kit further comprises a pharmaceutical composition comprising an inhibitor of prolactin secretion.
4. A pharmaceutical composition for treatment of breast or endometrial cancer comprising a therapeutically effective amount of an antiestrogen and of at least one pharmaceutical compound selected from the group consisting of an inhibitor of sex steroid formation chosen from the group consisting of an inhibitor of aromotase, an inhibitor of 30 - hydroxysteroid δ 5 -Δ-isomerase and an inhibitor of I7S estradiol dehydrogenase, an inhibitor of ACTH secretion and an inhibitor of growth hormone secretion.
5. · A pharmaceutical composition for treatment of breast or endometrial cancer including a pharmaceutical composition comprising an inhibitor of ovarian hormonal secretions, a pharmaceutical composition comprising an antiestrogen, and at least one pharmaceutical composition comprising a compound selected from th® group consisting of an inhibitor of sex steroid formation chosen from the group consisting of an inhibitor of aromotase, an inhibitor of 3{3 hydroxysteroid δ s -δ 4 -isomerase and an inhibitor of 170 - estradiol dehydrogenase, an androgenic compound, an inhibitor of growth hormone secretion and an inhibitor of ACTH secretion.
6. A composition according to Claim 4 or Claim 5 wherein said composition further comprises an, inhibitor of prolactin secretion.
7. A kit according to Claim 2 wherein both an androgenic compound and a non-adrenal inhibitor of sex steroid formation are included.
8. A composition according to Claim 5 wherein said composition includes both an androgenic compound and a non-adrenal inhibitor of sex steroid formation.
9. A kit for treatment of breast and endometrial cancer according to Claim 1 or Claim 2, substantially as herein described.
10. '10. A pharmaceutical composition for treatment of breast or endometrial cancer according to Claim 4 or Claim 5, substantially as herein described.
IE84690A 1989-03-10 1990-03-09 Combination therapy for treatment of estrogen sensitive diseases IE62715B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US32192689A 1989-03-10 1989-03-10

Publications (2)

Publication Number Publication Date
IE900846L IE900846L (en) 1990-09-10
IE62715B1 true IE62715B1 (en) 1995-02-22

Family

ID=23252650

Family Applications (1)

Application Number Title Priority Date Filing Date
IE84690A IE62715B1 (en) 1989-03-10 1990-03-09 Combination therapy for treatment of estrogen sensitive diseases

Country Status (17)

Country Link
US (1) US5550107A (en)
EP (1) EP0462189B1 (en)
JP (1) JP2959838B2 (en)
AT (1) ATE128362T1 (en)
AU (2) AU5281990A (en)
CA (1) CA2050291C (en)
DE (1) DE69022722T2 (en)
DK (1) DK0462189T3 (en)
ES (1) ES2077675T3 (en)
HU (1) HU221589B (en)
IE (1) IE62715B1 (en)
IL (1) IL93693A (en)
MY (1) MY110016A (en)
NZ (2) NZ244499A (en)
PH (1) PH30747A (en)
WO (1) WO1990010462A1 (en)
ZA (1) ZA901847B (en)

Families Citing this family (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5393785A (en) * 1988-10-31 1995-02-28 Endorecherche, Inc. Therapeutic antiestrogens
US5204337A (en) * 1988-10-31 1993-04-20 Endorecherche Inc. Estrogen nucleus derivatives for use in inhibition of sex steroid activity
US5395842A (en) * 1988-10-31 1995-03-07 Endorecherche Inc. Anti-estrogenic compounds and compositions
US5686465A (en) * 1988-10-31 1997-11-11 Endorecherche Inc. Sex steroid activity inhibitors
US5595985A (en) * 1989-03-10 1997-01-21 Endorecherche Inc. Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia
CA2062792C (en) * 1989-07-07 2006-03-21 Fernard Labrie Treatment of androgen-related diseases
IL101243A (en) * 1991-03-20 1999-12-22 Merck & Co Inc Pharmaceutical compositions for treatment of benign prostatic hyperplasia comprising a steroid derivative
US5340586A (en) * 1991-04-12 1994-08-23 University Of Southern California Methods and formulations for use in treating oophorectomized women
ZA924811B (en) * 1991-06-28 1993-12-29 Endorecherche Inc Controlled release systems and low dose androgens
HU222501B1 (en) * 1991-06-28 2003-07-28 Endorecherche Inc. Controlled release pharmaceutical composition containing mpa or mga and process for its preparation
US6060503A (en) * 1991-12-02 2000-05-09 Endorecherche, Inc. Benzopyran-containing compounds and method for their use
US5776923A (en) * 1993-01-19 1998-07-07 Endorecherche, Inc. Method of treating or preventing osteoporosis by adminstering dehydropiandrosterone
CN1100541C (en) * 1993-01-19 2003-02-05 恩多研究公司 Therapeutic uses and delivery systems of dehydroepiandrosterone
US5855920A (en) * 1996-12-13 1999-01-05 Chein; Edmund Y. M. Total hormone replacement therapy
US6653297B1 (en) * 1997-07-03 2003-11-25 Medical College Of Hampton Roads Control of selective estrogen receptor modulators
US6326392B1 (en) 1997-11-06 2001-12-04 American Home Products Corporation Anti-estrogen plus progestin containing oral contraceptives
US5879711A (en) * 1997-11-07 1999-03-09 Sequeira; Joel A. Stable antiandrogenic gel composition
CN1429104A (en) * 1998-03-11 2003-07-09 内部研究股份有限公司 Inhibitors type 5 and type 3 17 beta-hydroxysteroid dehydrogenase and methods for their use
US6069153A (en) * 1998-05-12 2000-05-30 American Home Products Corporation Indenoindoles and benzocarbazoles as estrogenic agents
US6479535B1 (en) * 1998-05-15 2002-11-12 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations
CA2331318A1 (en) * 1998-05-15 1999-11-25 James Harrison Pickar Compositions comprising 2-phenyl-indole compounds and estrogen formulations
US6465445B1 (en) * 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US7005428B1 (en) 1998-06-11 2006-02-28 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
AU4701299A (en) * 1998-06-23 2000-01-10 Stuart R. Adler Therapeutic applications of estrogenic carboxylic acids
US8173592B1 (en) 1999-03-31 2012-05-08 Zentaris Ivf Gmbh Method for a programmed controlled ovarian stimulation protocol
US6159959A (en) * 1999-05-06 2000-12-12 American Home Products Corporation Combined estrogen and antiestrogen therapy
AU2004222794B2 (en) * 1999-06-11 2007-03-08 Watson Pharmaceuticals, Inc. Non-oral androgenic steroids for women
PL352250A1 (en) * 1999-06-11 2003-08-11 Watson Pharmaceuticals Administration of non-oral androgenic steroids to women
US6187750B1 (en) 1999-08-25 2001-02-13 Everyoung Technologies, Inc. Method of hormone treatment for patients with symptoms consistent with multiple sclerosis
US6562790B2 (en) 2000-02-05 2003-05-13 Chein Edmund Y M Hormone therapy methods and hormone products for abating coronary artery blockage
US20040077605A1 (en) * 2001-06-20 2004-04-22 Salvati Mark E. Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
CZ20024214A3 (en) 2000-06-28 2003-04-16 Bristol-Myers Squibb Company Selective androgen receptor modulator, method of its identification, its construction, and use
US7001911B2 (en) 2000-06-28 2006-02-21 Bristol-Myers Squibb Company Fused cyclic modulators of nuclear hormone receptor function
US20040092494A9 (en) * 2000-08-30 2004-05-13 Dudley Robert E. Method of increasing testosterone and related steroid concentrations in women
US20030139384A1 (en) * 2000-08-30 2003-07-24 Dudley Robert E. Method for treating erectile dysfunction and increasing libido in men
US6503894B1 (en) 2000-08-30 2003-01-07 Unimed Pharmaceuticals, Inc. Pharmaceutical composition and method for treating hypogonadism
US6953679B2 (en) 2000-09-19 2005-10-11 Bristol-Myers Squibb Company Method for the preparation of fused heterocyclic succinimide compounds and analogs thereof
EP1854798A3 (en) * 2000-09-19 2007-11-28 Bristol-Myers Squibb Company Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
BR0114655A (en) * 2000-10-06 2004-02-10 Biomedicines Inc Method for identifying a combination of drugs for breast cancer treatment in an animal, Method for identifying a combination of breast cancer drugs in an animal, Method for identifying a combination of drugs for breast cancer prevention in an animal predisposed to said cancer, method for preventing breast cancer in an animal predisposed to said cancer, method for optimizing treatment of a breast cancer patient, method for optimizing a cancer prevention regimen in an animal, set useful for treating breast cancer in a patient in need of pharmaceutical composition and treatment for treating or preventing breast cancer
US20040087548A1 (en) 2001-02-27 2004-05-06 Salvati Mark E. Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
GB2375958B (en) * 2001-04-09 2005-03-02 George Margetts The use of steroids to lower the levels of cortisol
AU2002259147A1 (en) 2001-05-08 2002-11-18 Schering Corporation Use of neurokinin receptor antagonists to treat androgen-dependent diseases
DE10141937A1 (en) * 2001-08-28 2003-03-27 Alfred Schmidt Labeling the aromatase
CN1551878B (en) 2001-09-06 2011-08-10 先灵公司 17 beta-hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases
EP1436281B1 (en) 2001-10-17 2010-06-16 Schering Corporation Piperidine- and piperazineacetamides as 17beta hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases
US20040043938A1 (en) * 2001-11-06 2004-03-04 Dinesh Purandare Combination therapy for estrogen-dependent disorders
PL206962B1 (en) * 2001-12-19 2010-10-29 Bristol Myers Squibb Co Fused heterocyclic compounds and analogs thereof: modulators of nuclear hormone receptor function
JP2004002321A (en) * 2002-03-11 2004-01-08 Takeda Chem Ind Ltd Therapeutic agent for sex hormone dependent disease
US20050159361A1 (en) * 2002-03-11 2005-07-21 Takahito Hara Remedies for sex hormone-dependent disease
BR0308584A (en) * 2002-03-15 2005-02-22 Unimed Pharmaceuticals Inc Androgenic pharmaceutical composition and method for treating depression
US8569275B2 (en) 2002-08-28 2013-10-29 Harbor Therapeutics, Inc. Steroids having 7-oxgen and 17-heteroaryl substitution
CN100374421C (en) 2002-11-18 2008-03-12 先灵公司 17beta-hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases
MXPA05006485A (en) 2002-12-17 2005-08-26 Schering Corp 17 beta-hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases.
GB0302572D0 (en) * 2003-02-05 2003-03-12 Astrazeneca Ab Method of treatment
GB2400554B (en) * 2003-04-16 2007-04-18 George Margetts Treatment of angiotensin II-induced cardiovascular disease
CN102406650A (en) 2004-10-20 2012-04-11 恩多研究公司 Sex steroid precursors alone or in combination with selective estrogen receptor modulator for prevention and treatment of vaginal dryness and sexual dysfunction in postmenop
GB0513702D0 (en) 2005-07-04 2005-08-10 Sterix Ltd Compound
PT1937276E (en) 2005-10-12 2013-02-21 Besins Healthcare Luxembourg Improved testosterone gel and method of use
WO2007045027A1 (en) * 2005-10-19 2007-04-26 Chavah Pty Ltd Reduction of side effects from aromatase inhibitors used for treating breast cancer
US20100087407A1 (en) * 2006-08-04 2010-04-08 James Symons use of aromatase inhibitors
US8268806B2 (en) 2007-08-10 2012-09-18 Endorecherche, Inc. Pharmaceutical compositions
GB0722779D0 (en) 2007-11-20 2008-01-02 Sterix Ltd Compound
WO2009075838A2 (en) * 2007-12-10 2009-06-18 Meditrina Pharmaceuticals, Inc. Treatment of menorrhagia with aromatase inhibitor
KR101731008B1 (en) 2010-06-16 2017-04-27 앙도르쉐르슈 인코포레이티드 Methods of treating or preventing estrogen-related diseases
CA2965372C (en) 2014-10-22 2023-09-05 Havah Therapeutics Pty Ltd Methods of reducing mammographic breast density and/or breast cancer risk
CA3002562A1 (en) 2015-10-22 2017-04-27 Havah Therapeutics Pty Ltd Methods of reducing mammographic breast density and/or breast cancer risk
EP3976048A4 (en) 2019-06-03 2023-07-12 Havah Therapeutics Pty Ltd Pharmaceutical formulations and systems for delivery of an androgenic agent and an aromatase inhibitor and methods for use

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3061616A (en) * 1958-04-24 1962-10-30 Farmaceutici Italia Steroids, 6-methyl-17-hydroxy-progesterone and esters thereof, and a process for their preparation
US3127427A (en) * 1962-07-17 1964-03-31 Hoffmann La Roche 10-alkenyl-steroids and process therefor
CH507249A (en) * 1968-05-31 1971-05-15 Sandoz Ag Process for the preparation of 2-bromo-a-ergocryptine
DE2438350C3 (en) * 1974-08-09 1979-06-13 Hoechst Ag, 6000 Frankfurt Peptides with a strong LH-RH / FSH-RH action, process for their production and pharmaceutical preparations containing them
US4071622A (en) * 1976-02-11 1978-01-31 Abbott Laboratories Treatment of a mammary or DMBA inducible tumor
DE2617646C2 (en) * 1976-04-22 1986-07-31 Hoechst Ag, 6230 Frankfurt Nonapeptide-amides and decapeptide-amides with gonadoliberin activity, processes for their preparation and pharmaceutical preparations containing these compounds
GB1524747A (en) * 1976-05-11 1978-09-13 Ici Ltd Polypeptide
DE2658307C2 (en) * 1976-12-22 1979-03-15 Klinge Pharma Gmbh & Co, 8000 Muenchen Di-O'-hydroxyphenyD-alkane compounds, process for their preparation and their use as medicaments
FR2465486A1 (en) * 1979-09-21 1981-03-27 Roussel Uclaf NEW APPLICATION USING LH-RH OR AGONISTS
IE52535B1 (en) * 1981-02-16 1987-12-09 Ici Plc Continuous release pharmaceutical compositions
GB2108486B (en) * 1981-10-26 1986-01-29 Farmos Group Ltd Alkane and alkene derivatives and their preparation and use
US4481190A (en) * 1982-12-21 1984-11-06 Syntex (U.S.A.) Inc. Nonapeptide and decapeptide analogs of LHRH useful as LHRH antagonists
GB8311678D0 (en) * 1983-04-28 1983-06-02 Ici Plc Phenol derivatives
US4826831A (en) * 1983-08-05 1989-05-02 Pre Jay Holdings Limited Method of hormonal treatment for menopausal or post-menopausal disorders involving continuous administration of progestogens and estrogens
GB8327256D0 (en) * 1983-10-12 1983-11-16 Ici Plc Steroid derivatives
FR2558373B1 (en) * 1984-01-20 1987-07-03 Mauvais Jarvis Pierre ANTI-ESTROGEN MEDICINAL PRODUCT BASED ON 4-HYDROXYTAMOXIFENE FOR PERCUTANEOUS ADMINISTRATION
GB8410901D0 (en) * 1984-04-27 1984-06-06 Ici Plc Phenol derivatives
IE58417B1 (en) * 1984-04-27 1993-09-22 Ici Plc Chemical derivatives
US4666885A (en) * 1985-02-08 1987-05-19 Fernand Labrie Combination therapy for treatment of female breast cancer
US4760053A (en) * 1984-08-02 1988-07-26 Fernand Labrie Combination therapy for selected sex steroid dependent cancers
US4775660A (en) * 1984-08-02 1988-10-04 Fernand Labrie Treatment of breast cancer by combination therapy
EP0195015B1 (en) * 1984-08-02 1992-05-13 LABRIE, Fernand Pharmaceutical composition for combination therapy of hormone dependent cancers
US4650787A (en) * 1985-04-25 1987-03-17 Schally Andrew Victor Biologically active octapeptides
CN1021196C (en) * 1986-12-29 1993-06-16 新泽西州州立大学(鲁杰斯) Prepn. method of progestin unit and system
US4816258A (en) * 1987-02-26 1989-03-28 Alza Corporation Transdermal contraceptive formulations

Also Published As

Publication number Publication date
JP2959838B2 (en) 1999-10-06
HUT59836A (en) 1992-07-28
IL93693A0 (en) 1990-12-23
US5550107A (en) 1996-08-27
AU669767B2 (en) 1996-06-20
AU5513194A (en) 1994-04-28
CA2050291A1 (en) 1990-09-11
ES2077675T3 (en) 1995-12-01
NZ232870A (en) 1994-01-26
ATE128362T1 (en) 1995-10-15
IL93693A (en) 2000-01-31
HU902847D0 (en) 1991-11-28
JPH04504848A (en) 1992-08-27
AU5281990A (en) 1990-10-09
EP0462189A1 (en) 1991-12-27
HU221589B (en) 2002-11-28
IE900846L (en) 1990-09-10
NZ244499A (en) 1999-05-28
DE69022722T2 (en) 1996-05-02
ZA901847B (en) 1991-10-30
DE69022722D1 (en) 1995-11-02
WO1990010462A1 (en) 1990-09-20
DK0462189T3 (en) 1995-11-20
MY110016A (en) 1997-11-29
EP0462189B1 (en) 1995-09-27
CA2050291C (en) 2000-12-19
PH30747A (en) 1997-10-17

Similar Documents

Publication Publication Date Title
US5550107A (en) Combination therapy for the treatment of estrogen-sensitive disease
AU643445B2 (en) Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia
US5595985A (en) Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia
EP0595796B1 (en) Method of treatment of androgen-related diseases
AU594309B2 (en) Pharmaceutical composition for combination therapy of hormonedependent cancers
US4666885A (en) Combination therapy for treatment of female breast cancer
JP6532754B2 (en) Methods for treating or preventing estrogen related diseases
CA1278748C (en) Pharmaceutical composition for combination therapy of hormone dependent cancers

Legal Events

Date Code Title Description
MK9A Patent expired